Cullin-RING Ubiquitin Ligases in Neurodevelopment and Neurodevelopmental Disorders
Abstract
:1. Introduction
2. Human Genetics of CRL in NDD Patients
3. Behavioral Phenotypes of Mice with CRL Mutations
4. CRLs in Neural Stem Cell Proliferation and Differentiation
5. CRLs in Neuronal Polarization
6. CRLs in Neuronal Migration
7. CRLs in Synaptogenesis and Synaptic Function
8. Therapeutic Implications and Future Directions
9. Concluding Remarks
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Glickman, M.H.; Ciechanover, A. The ubiquitin-proteasome proteolytic pathway: Destruction for the sake of construction. Physiol. Rev. 2002, 82, 373–428. [Google Scholar] [CrossRef] [PubMed]
- Chen, Z.J.; Sun, L.J. Nonproteolytic functions of ubiquitin in cell signaling. Mol. Cell 2009, 33, 275–286. [Google Scholar] [CrossRef] [PubMed]
- Hershko, A.; Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 1998, 67, 425–479. [Google Scholar] [CrossRef] [PubMed]
- Metzger, M.B.; Hristova, V.A.; Weissman, A.M. HECT and RING finger families of E3 ubiquitin ligases at a glance. J. Cell Sci. 2012, 125 Pt 3, 531–537. [Google Scholar] [CrossRef]
- Uchida, C.; Kitagawa, M. RING-, HECT-, and RBR-type E3 Ubiquitin Ligases: Involvement in Human Cancer. Curr. Cancer Drug Targets 2016, 16, 157–174. [Google Scholar] [CrossRef]
- Zheng, N.; Shabek, N. Ubiquitin Ligases: Structure, Function, and Regulation. Annu. Rev. Biochem. 2017, 86, 129–157. [Google Scholar] [CrossRef]
- Damgaard, R.B. The ubiquitin system: From cell signalling to disease biology and new therapeutic opportunities. Cell Death Differ. 2021, 28, 423–426. [Google Scholar] [CrossRef]
- Petroski, M.D.; Deshaies, R.J. Function and regulation of cullin-RING ubiquitin ligases. Nat. Rev. Mol. Cell Biol. 2005, 6, 9–20. [Google Scholar] [CrossRef]
- Harper, J.W.; Schulman, B.A. Cullin-RING Ubiquitin Ligase Regulatory Circuits: A Quarter Century Beyond the F-Box Hypothesis. Annu. Rev. Biochem. 2021, 90, 403–429. [Google Scholar] [CrossRef]
- Skaar, J.R.; Pagan, J.K.; Pagano, M. Mechanisms and function of substrate recruitment by F-box proteins. Nat. Rev. Mol. Cell Biol. 2013, 14, 369–381. [Google Scholar] [CrossRef]
- Jackson, S.; Xiong, Y. CRL4s: The CUL4-RING E3 ubiquitin ligases. Trends Biochem. Sci. 2009, 34, 562–570. [Google Scholar] [CrossRef] [PubMed]
- Nakagawa, M.; Nakagawa, T. CUL4-Based Ubiquitin Ligases in Chromatin Regulation: An Evolutionary Perspective. Cells 2025, 14, 63. [Google Scholar] [CrossRef] [PubMed]
- Hopf, L.V.M.; Baek, K.; Klügel, M.; von Gronau, S.; Xiong, Y.; Schulman, B.A. Structure of CRL7(FBXW8) reveals coupling with CUL1-RBX1/ROC1 for multi-cullin-RING E3-catalyzed ubiquitin ligation. Nat. Struct. Mol. Biol. 2022, 29, 854–862. [Google Scholar] [CrossRef] [PubMed]
- Horn-Ghetko, D.; Hopf, L.V.M.; Tripathi-Giesgen, I.; Du, J.; Kostrhon, S.; Vu, D.T.; Beier, V.; Steigenberger, B.; Prabu, J.R.; Stier, L.; et al. Noncanonical assembly, neddylation and chimeric cullin-RING/RBR ubiquitylation by the 1.8 MDa CUL9 E3 ligase complex. Nat. Struct. Mol. Biol. 2024, 31, 1083–1094. [Google Scholar] [CrossRef]
- Kamura, T.; Maenaka, K.; Kotoshiba, S.; Matsumoto, M.; Kohda, D.; Conaway, R.C.; Conaway, J.W.; Nakayama, K.I. VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases. Genes. Dev. 2004, 18, 3055–3065. [Google Scholar] [CrossRef]
- Yamano, H. APC/C: Current understanding and future perspectives. F1000Research 2019, 8, 725. [Google Scholar] [CrossRef]
- Fuchsberger, T.; Lloret, A.; Viña, J. New Functions of APC/C Ubiquitin Ligase in the Nervous System and Its Role in Alzheimer’s Disease. Int. J. Mol. Sci. 2017, 18, 1057. [Google Scholar] [CrossRef]
- Banerjee-Basu, S.; Packer, A. SFARI Gene: An evolving database for the autism research community. Dis. Model Mech. 2010, 3, 133–135. [Google Scholar]
- Gentile, J.K.; Tan, W.H.; Horowitz, L.T.; Bacino, C.A.; Skinner, S.A.; Barbieri-Welge, R.; Bauer-Carlin, A.; Beaudet, A.L.; Bichell, T.J.; Lee, H.S.; et al. A neurodevelopmental survey of Angelman syndrome with genotype-phenotype correlations. J. Dev. Behav. Pediatr. 2010, 31, 592–601. [Google Scholar] [CrossRef]
- Vinci, M.; Treccarichi, S.; Galati Rando, R.; Musumeci, A.; Todaro, V.; Federico, C.; Saccone, S.; Elia, M.; Calì, F. A de novo ARIH2 gene mutation was detected in a patient with autism spectrum disorders and intellectual disability. Sci. Rep. 2024, 14, 15848. [Google Scholar] [CrossRef]
- De Rubeis, S.; He, X.; Goldberg, A.P.; Poultney, C.S.; Samocha, K.; Cicek, A.E.; Kou, Y.; Liu, L.; Fromer, M.; Walker, S.; et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 2014, 515, 209–215. [Google Scholar] [CrossRef] [PubMed]
- Al-Sarraj, Y.; Taha, R.Z.; Al-Dous, E.; Ahram, D.; Abbasi, S.; Abuazab, E.; Shaath, H.; Habbab, W.; Errafii, K.; Bejaoui, Y.; et al. The genetic landscape of autism spectrum disorder in the Middle Eastern population. Front. Genet. 2024, 15, 1363849. [Google Scholar] [CrossRef] [PubMed]
- Ebstein, F.; Küry, S.; Papendorf, J.J.; Krüger, E. Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): The Possible Contribution of Immune Dysregulation to Disease Pathogenesis. Front. Mol. Neurosci. 2021, 14, 733012. [Google Scholar] [CrossRef] [PubMed]
- Pinto, M.J.; Tomé, D.; Almeida, R.D. The Ubiquitinated Axon: Local Control of Axon Development and Function by Ubiquitin. J. Neurosci. 2021, 41, 2796–2813. [Google Scholar] [CrossRef]
- Ambrozkiewicz, M.C.; Lorenz, S. Understanding ubiquitination in neurodevelopment by integrating insights across space and time. Nat. Struct. Mol. Biol. 2025, 32, 14–22. [Google Scholar] [CrossRef]
- O’Roak, B.J.; Vives, L.; Fu, W.; Egertson, J.D.; Stanaway, I.B.; Phelps, I.G.; Carvill, G.; Kumar, A.; Lee, C.; Ankenman, K.; et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 2012, 338, 1619–1622. [Google Scholar] [CrossRef]
- Sanders, S.J.; He, X.; Willsey, A.J.; Ercan-Sencicek, A.G.; Samocha, K.E.; Cicek, A.E.; Murtha, M.T.; Bal, V.H.; Bishop, S.L.; Dong, S.; et al. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Neuron 2015, 87, 1215–1233. [Google Scholar] [CrossRef]
- Tarpey, P.S.; Raymond, F.L.; O’Meara, S.; Edkins, S.; Teague, J.; Butler, A.; Dicks, E.; Stevens, C.; Tofts, C.; Avis, T.; et al. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am. J. Hum. Genet. 2007, 80, 345–352. [Google Scholar] [CrossRef]
- Zou, Y.; Liu, Q.; Chen, B.; Zhang, X.; Guo, C.; Zhou, H.; Li, J.; Gao, G.; Guo, Y.; Yan, C.; et al. Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation. Am. J. Hum. Genet. 2007, 80, 561–566. [Google Scholar] [CrossRef]
- O’Roak, B.J.; Vives, L.; Girirajan, S.; Karakoc, E.; Krumm, N.; Coe, B.P.; Levy, R.; Ko, A.; Lee, C.; Smith, J.D.; et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 2012, 485, 246–250. [Google Scholar] [CrossRef]
- Gregor, A.; Sadleir, L.G.; Asadollahi, R.; Azzarello-Burri, S.; Battaglia, A.; Ousager, L.B.; Boonsawat, P.; Bruel, A.L.; Buchert, R.; Calpena, E.; et al. De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder. Am. J. Hum. Genet. 2018, 103, 305–316. [Google Scholar] [CrossRef] [PubMed]
- Gregor, A.; Meerbrei, T.; Gerstner, T.; Toutain, A.; Lynch, S.A.; Stals, K.; Maxton, C.; Lemke, J.R.; Bernat, J.A.; Bombei, H.M.; et al. De novo missense variants in FBXO11 alter its protein expression and subcellular localization. Hum. Mol. Genet. 2022, 31, 440–454. [Google Scholar] [CrossRef] [PubMed]
- Schneider, A.L.; Myers, C.T.; Muir, A.M.; Calvert, S.; Basinger, A.; Perry, M.S.; Rodan, L.; Helbig, K.L.; Chambers, C.; Gorman, K.M.; et al. FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability. Epilepsia 2021, 62, e13–e21. [Google Scholar] [CrossRef] [PubMed]
- Mir, A.; Sritharan, K.; Mittal, K.; Vasli, N.; Araujo, C.; Jamil, T.; Rafiq, M.A.; Anwar, Z.; Mikhailov, A.; Rauf, S.; et al. Truncation of the E3 ubiquitin ligase component FBXO31 causes non-syndromic autosomal recessive intellectual disability in a Pakistani family. Hum. Genet. 2014, 133, 975–984. [Google Scholar] [CrossRef]
- Harripaul, R.; Vasli, N.; Mikhailov, A.; Rafiq, M.A.; Mittal, K.; Windpassinger, C.; Sheikh, T.I.; Noor, A.; Mahmood, H.; Downey, S.; et al. Mapping autosomal recessive intellectual disability: Combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families. Mol. Psychiatry 2018, 23, 973–984. [Google Scholar] [CrossRef]
- Ansar, M.; Paracha, S.A.; Serretti, A.; Sarwar, M.T.; Khan, J.; Ranza, E.; Falconnet, E.; Iwaszkiewicz, J.; Shah, S.F.; Qaisar, A.A.; et al. Biallelic variants in FBXL3 cause intellectual disability, delayed motor development and short stature. Hum. Mol. Genet. 2019, 28, 972–979. [Google Scholar] [CrossRef]
- Bonnen, P.E.; Yarham, J.W.; Besse, A.; Wu, P.; Faqeih, E.A.; Al-Asmari, A.M.; Saleh, M.A.; Eyaid, W.; Hadeel, A.; He, L.; et al. Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance. Am. J. Hum. Genet. 2013, 93, 471–481. [Google Scholar] [CrossRef]
- Gai, X.; Ghezzi, D.; Johnson, M.A.; Biagosch, C.A.; Shamseldin, H.E.; Haack, T.B.; Reyes, A.; Tsukikawa, M.; Sheldon, C.A.; Srinivasan, S.; et al. Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy. Am. J. Hum. Genet. 2013, 93, 482–495. [Google Scholar] [CrossRef]
- Charng, W.L.; Karaca, E.; Coban Akdemir, Z.; Gambin, T.; Atik, M.M.; Gu, S.; Posey, J.E.; Jhangiani, S.N.; Muzny, D.M.; Doddapaneni, H.; et al. Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate. BMC Med. Genomics 2016, 9, 42. [Google Scholar] [CrossRef]
- Ruzzo, E.K.; Pérez-Cano, L.; Jung, J.Y.; Wang, L.K.; Kashef-Haghighi, D.; Hartl, C.; Singh, C.; Xu, J.; Hoekstra, J.N.; Leventhal, O.; et al. Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks. Cell 2019, 178, 850–866.e26. [Google Scholar] [CrossRef]
- Holt, R.J.; Young, R.M.; Crespo, B.; Ceroni, F.; Curry, C.J.; Bellacchio, E.; Bax, D.A.; Ciolfi, A.; Simon, M.; Fagerberg, C.R.; et al. De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies. Am. J. Hum. Genet. 2019, 105, 640–657. [Google Scholar] [CrossRef] [PubMed]
- Chau, K.K.; Zhang, P.; Urresti, J.; Amar, M.; Pramod, A.B.; Chen, J.; Thomas, A.; Corominas, R.; Lin, G.N.; Iakoucheva, L.M. Full-length isoform transcriptome of the developing human brain provides further insights into autism. Cell Rep. 2021, 36, 109631. [Google Scholar] [CrossRef] [PubMed]
- Stephenson, S.E.M.; Costain, G.; Blok, L.E.R.; Silk, M.A.; Nguyen, T.B.; Dong, X.; Alhuzaimi, D.E.; Dowling, J.J.; Walker, S.; Amburgey, K.; et al. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome. Am. J. Hum. Genet. 2022, 109, 601–617. [Google Scholar] [CrossRef] [PubMed]
- Meier-Abt, F.; Kraemer, D.; Braun, N.; Reinehr, M.; Stutz-Grunder, E.; Steindl, K.; Rauch, A. Further evidence that the neurodevelopmental gene FBXW7 predisposes to Wilms tumor. Am. J. Med. Genet. A 2024, 194, e63528. [Google Scholar] [CrossRef]
- Wang, Y.; Ma, X.; Li, H.; Dai, Y.; Wang, X.; Liu, L. Case report: A novel FBXW7 gene variant causes global developmental delay. Front. Genet. 2024, 15, 1436462. [Google Scholar] [CrossRef]
- Mignon-Ravix, C.; Cacciagli, P.; Choucair, N.; Popovici, C.; Missirian, C.; Milh, M.; Mégarbané, A.; Busa, T.; Julia, S.; Girard, N.; et al. Intragenic rearrangements in X-linked intellectual deficiency: Results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes. Am. J. Med. Genet. A 2014, 164A, 1991–1997. [Google Scholar] [CrossRef]
- Sleyp, Y.; Valenzuela, I.; Accogli, A.; Ballon, K.; Ben-Zeev, B.; Berkovic, S.F.; Broly, M.; Callaerts, P.; Caylor, R.C.; Charles, P.; et al. De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder. Genet. Med. 2022, 24, 2464–2474. [Google Scholar] [CrossRef]
- Mastrangelo, M.; Sartori, S.; Simonati, A.; Brinciotti, M.; Moro, F.; Nosadini, M.; Pezzini, F.; Doccini, S.; Santorelli, F.M.; Leuzzi, V. Progressive myoclonus epilepsy and ceroidolipofuscinosis 14: The multifaceted phenotypic spectrum of KCTD7-related disorders. Eur. J. Med. Genet. 2019, 62, 103591. [Google Scholar] [CrossRef]
- Golzio, C.; Willer, J.; Talkowski, M.E.; Oh, E.C.; Taniguchi, Y.; Jacquemont, S.; Reymond, A.; Sun, M.; Sawa, A.; Gusella, J.F.; et al. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature 2012, 485, 363–367. [Google Scholar] [CrossRef]
- Clothier, J.L.; Grooms, A.N.; Porter-Gill, P.A.; Gill, P.S.; Schaefer, G.B. Identification of DCAF1 by Clinical Exome Sequencing and Methylation Analysis as a Candidate Gene for Autism and Intellectual Disability: A Case Report. J. Pers. Med. 2022, 12, 886. [Google Scholar] [CrossRef]
- Webster, E.; Cho, M.T.; Alexander, N.; Desai, S.; Naidu, S.; Bekheirnia, M.R.; Lewis, A.; Retterer, K.; Juusola, J.; Chung, W.K. De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features. Cold Spring Harb. Mol. Case Stud. 2016, 2, a001172. [Google Scholar] [CrossRef] [PubMed]
- Jansen, S.; Hoischen, A.; Coe, B.P.; Carvill, G.L.; Van Esch, H.; Bosch, D.G.M.; Andersen, U.A.; Baker, C.; Bauters, M.; Bernier, R.A.; et al. A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency. Eur. J. Hum. Genet. 2018, 26, 54–63. [Google Scholar] [CrossRef]
- Glessner, J.T.; Wang, K.; Cai, G.; Korvatska, O.; Kim, C.E.; Wood, S.; Zhang, H.; Estes, A.; Brune, C.W.; Bradfield, J.P.; et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 2009, 459, 569–573. [Google Scholar] [CrossRef] [PubMed]
- Higgins, J.J.; Pucilowska, J.; Lombardi, R.Q.; Rooney, J.P. A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation. Neurology 2004, 63, 1927–1931. [Google Scholar] [CrossRef]
- Sheereen, A.; Alaamery, M.; Bawazeer, S.; Al Yafee, Y.; Massadeh, S.; Eyaid, W. A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi family. J. Med. Genet. 2017, 54, 236–240. [Google Scholar] [CrossRef]
- Rodríguez, C.; Sánchez-Morán, I.; Álvarez, S.; Tirado, P.; Fernández-Mayoralas, D.M.; Calleja-Pérez, B.; Almeida, Á.; Fernández-Jaén, A. A novel human Cdh1 mutation impairs anaphase promoting complex/cyclosome activity resulting in microcephaly, psychomotor retardation, and epilepsy. J. Neurochem. 2019, 151, 103–115. [Google Scholar] [CrossRef]
- Gonzalez-Sulser, A. Rodent genetic models of neurodevelopmental disorders and epilepsy. Eur. J. Paediatr. Neurol. 2020, 24, 66–69. [Google Scholar] [CrossRef]
- Silverman, J.L.; Thurm, A.; Ethridge, S.B.; Soller, M.M.; Petkova, S.P.; Abel, T.; Bauman, M.D.; Brodkin, E.S.; Harony-Nicolas, H.; Wöhr, M.; et al. Reconsidering animal models used to study autism spectrum disorder: Current state and optimizing future. Genes. Brain Behav. 2022, 21, e12803. [Google Scholar] [CrossRef]
- Damianidou, E.; Mouratidou, L.; Kyrousi, C. Research models of neurodevelopmental disorders: The right model in the right place. Front. Neurosci. 2022, 16, 1031075. [Google Scholar] [CrossRef]
- Takao, K.; Yamasaki, N.; Miyakawa, T. Impact of brain-behavior phenotypying of genetically-engineered mice on research of neuropsychiatric disorders. Neurosci. Res. 2007, 58, 124–132. [Google Scholar] [CrossRef]
- Huang, L.; Xiao, D.; Sun, H.; Qu, Y.; Su, X. Behavioral tests for evaluating the characteristics of brain diseases in rodent models: Optimal choices for improved outcomes (Review). Mol. Med. Rep. 2022, 25, 183. [Google Scholar] [CrossRef] [PubMed]
- Amar, M.; Pramod, A.B.; Yu, N.K.; Herrera, V.M.; Qiu, L.R.; Moran-Losada, P.; Zhang, P.; Trujillo, C.A.; Ellegood, J.; Urresti, J.; et al. Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling. Mol. Psychiatry 2021, 26, 3586–3613. [Google Scholar] [CrossRef]
- Morandell, J.; Schwarz, L.A.; Basilico, B.; Tasciyan, S.; Dimchev, G.; Nicolas, A.; Sommer, C.; Kreuzinger, C.; Dotter, C.P.; Knaus, L.S.; et al. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nat. Commun. 2021, 12, 3058. [Google Scholar] [CrossRef]
- Dong, Z.; Chen, W.; Chen, C.; Wang, H.; Cui, W.; Tan, Z.; Robinson, H.; Gao, N.; Luo, B.; Zhang, L.; et al. CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by Impairing Excitation-Inhibition Balance through the Promotion of Cap-Dependent Translation. Neuron 2020, 105, 475–490.e6. [Google Scholar] [CrossRef]
- Gao, N.; Liu, Z.; Wang, H.; Shen, C.; Dong, Z.; Cui, W.; Xiong, W.C.; Mei, L. Deficiency of Cullin 3, a Protein Encoded by a Schizophrenia and Autism Risk Gene, Impairs Behaviors by Enhancing the Excitability of Ventral Tegmental Area (VTA) DA Neurons. J. Neurosci. 2023, 43, 6249–6267. [Google Scholar] [CrossRef]
- Chen, C.Y.; Tsai, M.S.; Lin, C.Y.; Yu, I.S.; Chen, Y.T.; Lin, S.R.; Juan, L.W.; Hsu, H.M.; Lee, L.J.; Lin, S.W. Rescue of the genetically engineered Cul4b mutant mouse as a potential model for human X-linked mental retardation. Hum. Mol. Genet. 2012, 21, 4270–4285. [Google Scholar] [CrossRef]
- Hu, H.T.; Huang, T.N.; Hsueh, Y.P. KLHL17/Actinfilin, a brain-specific gene associated with infantile spasms and autism, regulates dendritic spine enlargement. J. Biomed. Sci. 2020, 27, 103. [Google Scholar] [CrossRef]
- Arbogast, T.; Razaz, P.; Ellegood, J.; McKinstry, S.U.; Erdin, S.; Currall, B.; Aneichyk, T.; Lerch, J.P.; Qiu, L.R.; Rodriguiz, R.M.; et al. Kctd13-deficient mice display short-term memory impairment and sex-dependent genetic interactions. Hum. Mol. Genet. 2019, 28, 1474–1486. [Google Scholar] [CrossRef]
- Rajadhyaksha, A.M.; Ra, S.; Kishinevsky, S.; Lee, A.S.; Romanienko, P.; DuBoff, M.; Yang, C.; Zupan, B.; Byrne, M.; Daruwalla, Z.R.; et al. Behavioral characterization of cereblon forebrain-specific conditional null mice: A model for human non-syndromic intellectual disability. Behav. Brain Res. 2012, 226, 428–434. [Google Scholar] [CrossRef]
- Li, M.; Shin, Y.H.; Hou, L.; Huang, X.; Wei, Z.; Klann, E.; Zhang, P. The adaptor protein of the anaphase promoting complex Cdh1 is essential in maintaining replicative lifespan and in learning and memory. Nat. Cell Biol. 2008, 10, 1083–1089. [Google Scholar] [CrossRef] [PubMed]
- Bobo-Jiménez, V.; Delgado-Esteban, M.; Angibaud, J.; Sánchez-Morán, I.; de la Fuente, A.; Yajeya, J.; Nägerl, U.V.; Castillo, J.; Bolaños, J.P.; Almeida, A. APC/C(Cdh1)-Rock2 pathway controls dendritic integrity and memory. Proc. Natl. Acad. Sci. USA 2017, 114, 4513–4518. [Google Scholar] [CrossRef] [PubMed]
- Navarro Negredo, P.; Yeo, R.W.; Brunet, A. Aging and Rejuvenation of Neural Stem Cells and Their Niches. Cell Stem Cell 2020, 27, 202–223. [Google Scholar] [CrossRef] [PubMed]
- Alonso, M.; Petit, A.C.; Lledo, P.M. The impact of adult neurogenesis on affective functions: Of mice and men. Mol. Psychiatry 2024, 29, 2527–2542. [Google Scholar] [CrossRef] [PubMed]
- Florio, M.; Huttner, W.B. Neural progenitors, neurogenesis and the evolution of the neocortex. Development 2014, 141, 2182–2194. [Google Scholar] [CrossRef]
- Taverna, E.; Götz, M.; Huttner, W.B. The cell biology of neurogenesis: Toward an understanding of the development and evolution of the neocortex. Annu. Rev. Cell Dev. Biol. 2014, 30, 465–502. [Google Scholar] [CrossRef]
- Zhou, Y.; Song, H.; Ming, G.L. Genetics of human brain development. Nat. Rev. Genet. 2024, 25, 26–45. [Google Scholar] [CrossRef]
- Pines, J. Cubism and the cell cycle: The many faces of the APC/C. Nat. Rev. Mol. Cell Biol. 2011, 12, 427–438. [Google Scholar] [CrossRef]
- Delgado-Esteban, M.; García-Higuera, I.; Maestre, C.; Moreno, S.; Almeida, A. APC/C-Cdh1 coordinates neurogenesis and cortical size during development. Nat. Commun. 2013, 4, 2879. [Google Scholar] [CrossRef]
- Capecchi, M.R.; Pozner, A. ASPM regulates symmetric stem cell division by tuning Cyclin E ubiquitination. Nat. Commun. 2015, 6, 8763. [Google Scholar] [CrossRef]
- Matsumoto, A.; Onoyama, I.; Sunabori, T.; Kageyama, R.; Okano, H.; Nakayama, K.I. Fbxw7-dependent degradation of Notch is required for control of “stemness” and neuronal-glial differentiation in neural stem cells. J. Biol. Chem. 2011, 286, 13754–13764. [Google Scholar] [CrossRef]
- MacDonald, B.T.; Tamai, K.; He, X. Wnt/beta-catenin signaling: Components, mechanisms, and diseases. Dev. Cell 2009, 17, 9–26. [Google Scholar] [CrossRef] [PubMed]
- Liu, J.; Xiao, Q.; Xiao, J.; Niu, C.; Li, Y.; Zhang, X.; Zhou, Z.; Shu, G.; Yin, G. Wnt/β-catenin signalling: Function, biological mechanisms, and therapeutic opportunities. Signal Transduct. Target. Ther. 2022, 7, 3. [Google Scholar] [CrossRef] [PubMed]
- Cui, C.P.; Zhang, Y.; Wang, C.; Yuan, F.; Li, H.; Yao, Y.; Chen, Y.; Li, C.; Wei, W.; Liu, C.H.; et al. Dynamic ubiquitylation of Sox2 regulates proteostasis and governs neural progenitor cell differentiation. Nat. Commun. 2018, 9, 4648. [Google Scholar] [CrossRef] [PubMed]
- Bond, J.; Scott, S.; Hampshire, D.J.; Springell, K.; Corry, P.; Abramowicz, M.J.; Mochida, G.H.; Hennekam, R.C.; Maher, E.R.; Fryns, J.P.; et al. Protein-truncating mutations in ASPM cause variable reduction in brain size. Am. J. Hum. Genet. 2003, 73, 1170–1177. [Google Scholar] [CrossRef] [PubMed]
- Létard, P.; Drunat, S.; Vial, Y.; Duerinckx, S.; Ernault, A.; Amram, D.; Arpin, S.; Bertoli, M.; Busa, T.; Ceulemans, B.; et al. Autosomal recessive primary microcephaly due to ASPM mutations: An update. Hum. Mutat. 2018, 39, 319–332. [Google Scholar] [CrossRef]
- Arimura, N.; Kaibuchi, K. Neuronal polarity: From extracellular signals to intracellular mechanisms. Nat. Rev. Neurosci. 2007, 8, 194–205. [Google Scholar] [CrossRef]
- Yogev, S.; Shen, K. Establishing Neuronal Polarity with Environmental and Intrinsic Mechanisms. Neuron 2017, 96, 638–650. [Google Scholar] [CrossRef]
- Jung, M.; Kim, D.; Mun, J.Y. Direct Visualization of Actin Filaments and Actin-Binding Proteins in Neuronal Cells. Front. Cell Dev. Biol. 2020, 8, 588556. [Google Scholar] [CrossRef]
- Meka, D.P.; Kobler, O.; Hong, S.; Friedrich, C.M.; Wuesthoff, S.; Henis, M.; Schwanke, B.; Krisp, C.; Schmuelling, N.; Rueter, R.; et al. Centrosome-dependent microtubule modifications set the conditions for axon formation. Cell Rep. 2022, 39, 110686. [Google Scholar] [CrossRef]
- Yoshimura, T.; Arimura, N.; Kaibuchi, K. Signaling networks in neuronal polarization. J. Neurosci. 2006, 26, 10626–10630. [Google Scholar] [CrossRef]
- Lee, Y.R.; Chen, M.; Pandolfi, P.P. The functions and regulation of the PTEN tumour suppressor: New modes and prospects. Nat. Rev. Mol. Cell Biol. 2018, 19, 547–562. [Google Scholar] [CrossRef] [PubMed]
- Christie, K.J.; Martinez, J.A.; Zochodne, D.W. Disruption of E3 ligase NEDD4 in peripheral neurons interrupts axon outgrowth: Linkage to PTEN. Mol. Cell Neurosci. 2012, 50, 179–192. [Google Scholar] [CrossRef] [PubMed]
- Drinjakovic, J.; Jung, H.; Campbell, D.S.; Strochlic, L.; Dwivedy, A.; Holt, C.E. E3 ligase Nedd4 promotes axon branching by downregulating PTEN. Neuron 2010, 65, 341–357. [Google Scholar] [CrossRef]
- Hsia, H.E.; Kumar, R.; Luca, R.; Takeda, M.; Courchet, J.; Nakashima, J.; Wu, S.; Goebbels, S.; An, W.; Eickholt, B.J.; et al. Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth. Proc. Natl. Acad. Sci. USA 2014, 111, 13205–13210. [Google Scholar] [CrossRef]
- Chen, Z.; Zhang, W.; Jiang, K.; Chen, B.; Wang, K.; Lao, L.; Hou, C.; Wang, F.; Zhang, C.; Shen, H. MicroRNA-300 Regulates the Ubiquitination of PTEN through the CRL4B(DCAF13) E3 Ligase in Osteosarcoma Cells. Mol. Ther. Nucleic Acids 2018, 10, 254–268. [Google Scholar] [CrossRef]
- Zhang, J.; Zhang, Y.L.; Zhao, L.W.; Pi, S.B.; Zhang, S.Y.; Tong, C.; Fan, H.Y. The CRL4-DCAF13 ubiquitin E3 ligase supports oocyte meiotic resumption by targeting PTEN degradation. Cell Mol. Life Sci. 2020, 77, 2181–2197. [Google Scholar] [CrossRef]
- Ge, M.K.; Zhang, N.; Xia, L.; Zhang, C.; Dong, S.S.; Li, Z.M.; Ji, Y.; Zheng, M.H.; Sun, J.; Chen, G.Q.; et al. FBXO22 degrades nuclear PTEN to promote tumorigenesis. Nat. Commun. 2020, 11, 1720. [Google Scholar] [CrossRef]
- Dupraz, S.; Hilton, B.J.; Husch, A.; Santos, T.E.; Coles, C.H.; Stern, S.; Brakebusch, C.; Bradke, F. RhoA Controls Axon Extension Independent of Specification in the Developing Brain. Curr. Biol. 2019, 29, 3874–3886.e9. [Google Scholar] [CrossRef]
- Kannan, M.; Lee, S.J.; Schwedhelm-Domeyer, N.; Stegmüller, J. The E3 ligase Cdh1-anaphase promoting complex operates upstream of the E3 ligase Smurf1 in the control of axon growth. Development 2012, 139, 3600–3612. [Google Scholar] [CrossRef]
- Lin, M.Y.; Lin, Y.M.; Kao, T.C.; Chuang, H.H.; Chen, R.H. PDZ-RhoGEF ubiquitination by Cullin3-KLHL20 controls neurotrophin-induced neurite outgrowth. J. Cell Biol. 2011, 193, 985–994. [Google Scholar] [CrossRef]
- Dogterom, M.; Koenderink, G.H. Actin-microtubule crosstalk in cell biology. Nat. Rev. Mol. Cell Biol. 2019, 20, 38–54. [Google Scholar] [CrossRef] [PubMed]
- Song, J.; Merrill, R.A.; Usachev, A.Y.; Strack, S. The X-linked intellectual disability gene product and E3 ubiquitin ligase KLHL15 degrades doublecortin proteins to constrain neuronal dendritogenesis. J. Biol. Chem. 2021, 296, 100082. [Google Scholar] [CrossRef] [PubMed]
- Shim, T.; Kim, J.Y.; Kim, W.; Lee, Y.I.; Cho, B.; Moon, C. Cullin-RING E3 ubiquitin ligase 4 regulates neurite morphogenesis during neurodevelopment. iScience 2024, 27, 108933. [Google Scholar] [CrossRef] [PubMed]
- Stegmüller, J.; Konishi, Y.; Huynh, M.A.; Yuan, Z.; Dibacco, S.; Bonni, A. Cell-intrinsic regulation of axonal morphogenesis by the Cdh1-APC target SnoN. Neuron 2006, 50, 389–400. [Google Scholar] [CrossRef]
- Lasorella, A.; Stegmüller, J.; Guardavaccaro, D.; Liu, G.; Carro, M.S.; Rothschild, G.; de la Torre-Ubieta, L.; Pagano, M.; Bonni, A.; Iavarone, A. Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature 2006, 442, 471–474. [Google Scholar] [CrossRef]
- Nakagawa, T.; Xiong, Y. X-linked mental retardation gene CUL4B targets ubiquitylation of H3K4 methyltransferase component WDR5 and regulates neuronal gene expression. Mol. Cell 2011, 43, 381–391. [Google Scholar] [CrossRef]
- Nakagawa, T.; Xiong, Y. Chromatin regulation by CRL4 E3 ubiquitin ligases: CUL4B targets WDR5 ubiquitylation in the nucleus. Cell Cycle 2011, 10, 4197–4198. [Google Scholar]
- Shilatifard, A. The COMPASS family of histone H3K4 methylases: Mechanisms of regulation in development and disease pathogenesis. Annu. Rev. Biochem. 2012, 81, 65–95. [Google Scholar] [CrossRef]
- Green, E.M.; Gozani, O. CUL4B: Trash talking at chromatin. Mol. Cell 2011, 43, 321–323. [Google Scholar] [CrossRef]
- des Portes, V.; Pinard, J.M.; Billuart, P.; Vinet, M.C.; Koulakoff, A.; Carrié, A.; Gelot, A.; Dupuis, E.; Motte, J.; Berwald-Netter, Y.; et al. A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell 1998, 92, 51–61. [Google Scholar] [CrossRef]
- Gleeson, J.G.; Allen, K.M.; Fox, J.W.; Lamperti, E.D.; Berkovic, S.; Scheffer, I.; Cooper, E.C.; Dobyns, W.B.; Minnerath, S.R.; Ross, M.E.; et al. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 1998, 92, 63–72. [Google Scholar] [CrossRef] [PubMed]
- Butler, M.G.; Dasouki, M.J.; Zhou, X.P.; Talebizadeh, Z.; Brown, M.; Takahashi, T.N.; Miles, J.H.; Wang, C.H.; Stratton, R.; Pilarski, R.; et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J. Med. Genet. 2005, 42, 318–321. [Google Scholar] [CrossRef] [PubMed]
- Tan, M.H.; Mester, J.; Peterson, C.; Yang, Y.; Chen, J.L.; Rybicki, L.A.; Milas, K.; Pederson, H.; Remzi, B.; Orloff, M.S.; et al. A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. Am. J. Hum. Genet. 2011, 88, 42–56. [Google Scholar] [CrossRef] [PubMed]
- Agirman, G.; Broix, L.; Nguyen, L. Cerebral cortex development: An outside-in perspective. FEBS Lett. 2017, 591, 3978–3992. [Google Scholar] [CrossRef]
- Jossin, Y. Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation. Biomolecules 2020, 10, 964. [Google Scholar] [CrossRef]
- Joly-Amado, A.; Kulkarni, N.; Nash, K.R. Reelin Signaling in Neurodevelopmental Disorders and Neurodegenerative Diseases. Brain Sci. 2023, 13, 1479. [Google Scholar] [CrossRef]
- Gao, Z.; Godbout, R. Reelin-Disabled-1 signaling in neuronal migration: Splicing takes the stage. Cell Mol. Life Sci. 2013, 70, 2319–2329. [Google Scholar] [CrossRef]
- Feng, L.; Allen, N.S.; Simo, S.; Cooper, J.A. Cullin 5 regulates Dab1 protein levels and neuron positioning during cortical development. Genes. Dev. 2007, 21, 2717–2730. [Google Scholar] [CrossRef]
- Stier, A.; Gilberto, S.; Mohamed, W.I.; Royall, L.N.; Helenius, J.; Mikicic, I.; Sajic, T.; Beli, P.; Müller, D.J.; Jessberger, S.; et al. The CUL4B-based E3 ubiquitin ligase regulates mitosis and brain development by recruiting phospho-specific DCAFs. EMBO J. 2023, 42, e112847. [Google Scholar] [CrossRef]
- Butts, T.; Green, M.J.; Wingate, R.J. Development of the cerebellum: Simple steps to make a ‘little brain’. Development 2014, 141, 4031–4041. [Google Scholar] [CrossRef]
- Cossart, R.; Khazipov, R. How development sculpts hippocampal circuits and function. Physiol. Rev. 2022, 102, 343–378. [Google Scholar] [CrossRef] [PubMed]
- Mukherjee, C.; Holubowska, A.; Schwedhelm-Domeyer, N.; Mitkovski, M.; Lee, S.J.; Kannan, M.; Matz, A.; Vadhvani, M.; Stegmüller, J. Loss of the neuron-specific F-box protein FBXO41 models an ataxia-like phenotype in mice with neuronal migration defects and degeneration in the cerebellum. J. Neurosci. 2015, 35, 8701–8717. [Google Scholar] [CrossRef] [PubMed]
- Quadros, A.; Arazola, R.D.; Álvarez, A.R.; Pires, J.; Meredith, R.M.; Saarloos, I.; Verhage, M.; Toonen, R.F. Neuronal F-Box protein FBXO41 regulates synaptic transmission and hippocampal network maturation. iScience 2022, 25, 104069. [Google Scholar] [CrossRef] [PubMed]
- King, C.R.; AR, A.A.Q.; Chazeau, A.; Saarloos, I.; van der Graaf, A.J.; Verhage, M.; Toonen, R.F. Fbxo41 Promotes Disassembly of Neuronal Primary Cilia. Sci. Rep. 2019, 9, 8179. [Google Scholar] [CrossRef]
- Persico, A.M.; D’Agruma, L.; Maiorano, N.; Totaro, A.; Militerni, R.; Bravaccio, C.; Wassink, T.H.; Schneider, C.; Melmed, R.; Trillo, S.; et al. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol. Psychiatry 2001, 6, 150–159. [Google Scholar] [CrossRef]
- Skaar, D.A.; Shao, Y.; Haines, J.L.; Stenger, J.E.; Jaworski, J.; Martin, E.R.; DeLong, G.R.; Moore, J.H.; McCauley, J.L.; Sutcliffe, J.S.; et al. Analysis of the RELN gene as a genetic risk factor for autism. Mol. Psychiatry 2005, 10, 563–571. [Google Scholar] [CrossRef]
- Nawa, Y.; Kimura, H.; Mori, D.; Kato, H.; Toyama, M.; Furuta, S.; Yu, Y.; Ishizuka, K.; Kushima, I.; Aleksic, B.; et al. Rare single-nucleotide DAB1 variants and their contribution to Schizophrenia and autism spectrum disorder susceptibility. Hum. Genome Var. 2020, 7, 37. [Google Scholar] [CrossRef]
- Saillour, Y.; Carion, N.; Quelin, C.; Leger, P.L.; Boddaert, N.; Elie, C.; Toutain, A.; Mercier, S.; Barthez, M.A.; Milh, M.; et al. LIS1-related isolated lissencephaly: Spectrum of mutations and relationships with malformation severity. Arch. Neurol. 2009, 66, 1007–1015. [Google Scholar] [CrossRef]
- Südhof, T.C. Towards an Understanding of Synapse Formation. Neuron 2018, 100, 276–293. [Google Scholar] [CrossRef]
- Qi, C.; Luo, L.D.; Feng, I.; Ma, S. Molecular mechanisms of synaptogenesis. Front. Synaptic Neurosci. 2022, 14, 939793. [Google Scholar] [CrossRef]
- Kaizuka, T.; Takumi, T. Postsynaptic density proteins and their involvement in neurodevelopmental disorders. J. Biochem. 2018, 163, 447–455. [Google Scholar] [CrossRef] [PubMed]
- Yang, Y.; Kim, A.H.; Yamada, T.; Wu, B.; Bilimoria, P.M.; Ikeuchi, Y.; de la Iglesia, N.; Shen, J.; Bonni, A. A Cdc20-APC ubiquitin signaling pathway regulates presynaptic differentiation. Science 2009, 326, 575–578. [Google Scholar] [CrossRef] [PubMed]
- Kawabe, H.; Stegmüller, J. The role of E3 ubiquitin ligases in synapse function in the healthy and diseased brain. Mol. Cell Neurosci. 2021, 112, 103602. [Google Scholar] [CrossRef] [PubMed]
- Yao, I.; Takagi, H.; Ageta, H.; Kahyo, T.; Sato, S.; Hatanaka, K.; Fukuda, Y.; Chiba, T.; Morone, N.; Yuasa, S.; et al. SCRAPPER-dependent ubiquitination of active zone protein RIM1 regulates synaptic vesicle release. Cell 2007, 130, 943–957. [Google Scholar] [CrossRef]
- Hansen, K.B.; Wollmuth, L.P.; Bowie, D.; Furukawa, H.; Menniti, F.S.; Sobolevsky, A.I.; Swanson, G.T.; Swanger, S.A.; Greger, I.H.; Nakagawa, T.; et al. Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels. Pharmacol. Rev. 2021, 73, 298–487. [Google Scholar] [CrossRef]
- Niswender, C.M.; Conn, P.J. Metabotropic glutamate receptors: Physiology, pharmacology, and disease. Annu. Rev. Pharmacol. Toxicol. 2010, 50, 295–322. [Google Scholar] [CrossRef]
- Fu, A.K.; Hung, K.W.; Fu, W.Y.; Shen, C.; Chen, Y.; Xia, J.; Lai, K.O.; Ip, N.Y. APC(Cdh1) mediates EphA4-dependent downregulation of AMPA receptors in homeostatic plasticity. Nat. Neurosci. 2011, 14, 181–189. [Google Scholar] [CrossRef]
- Malenka, R.C.; Bear, M.F. LTP and LTD: An embarrassment of riches. Neuron 2004, 44, 5–21. [Google Scholar] [CrossRef]
- Huang, J.; Ikeuchi, Y.; Malumbres, M.; Bonni, A. A Cdh1-APC/FMRP Ubiquitin Signaling Link Drives mGluR-Dependent Synaptic Plasticity in the Mammalian Brain. Neuron 2015, 86, 726–739. [Google Scholar] [CrossRef]
- Gu, J.; Ke, P.; Guo, H.; Liu, J.; Liu, Y.; Tian, X.; Huang, Z.; Xu, X.; Xu, D.; Ma, Y.; et al. KCTD13-mediated ubiquitination and degradation of GluN1 regulates excitatory synaptic transmission and seizure susceptibility. Cell Death Differ. 2023, 30, 1726–1741. [Google Scholar] [CrossRef]
- Mandic-Maravic, V.; Grujicic, R.; Milutinovic, L.; Munjiza-Jovanovic, A.; Pejovic-Milovancevic, M. Dopamine in Autism Spectrum Disorders-Focus on D2/D3 Partial Agonists and Their Possible Use in Treatment. Front. Psychiatry 2021, 12, 787097. [Google Scholar] [CrossRef] [PubMed]
- Pavăl, D. The dopamine hypothesis of autism spectrum disorder: A comprehensive analysis of the evidence. Int. Rev. Neurobiol. 2023, 173, 1–42. [Google Scholar] [CrossRef] [PubMed]
- Maljevic, S.; Lerche, H. Potassium channels: A review of broadening therapeutic possibilities for neurological diseases. J. Neurol. 2013, 260, 2201–2211. [Google Scholar] [CrossRef] [PubMed]
- Simons, C.; Rash, L.D.; Crawford, J.; Ma, L.; Cristofori-Armstrong, B.; Miller, D.; Ru, K.; Baillie, G.J.; Alanay, Y.; Jacquinet, A.; et al. Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy. Nat. Genet. 2015, 47, 73–77. [Google Scholar] [CrossRef]
- Kortüm, F.; Caputo, V.; Bauer, C.K.; Stella, L.; Ciolfi, A.; Alawi, M.; Bocchinfuso, G.; Flex, E.; Paolacci, S.; Dentici, M.L.; et al. Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. Nat. Genet. 2015, 47, 661–667. [Google Scholar] [CrossRef]
- Hsu, P.H.; Ma, Y.T.; Fang, Y.C.; Huang, J.J.; Gan, Y.L.; Chang, P.T.; Jow, G.M.; Tang, C.Y.; Jeng, C.J. Cullin 7 mediates proteasomal and lysosomal degradations of rat Eag1 potassium channels. Sci. Rep. 2017, 7, 40825. [Google Scholar] [CrossRef]
- Rochefort, N.L.; Konnerth, A. Dendritic spines: From structure to in vivo function. EMBO Rep. 2012, 13, 699–708. [Google Scholar] [CrossRef]
- Soucy, T.A.; Smith, P.G.; Milhollen, M.A.; Berger, A.J.; Gavin, J.M.; Adhikari, S.; Brownell, J.E.; Burke, K.E.; Cardin, D.P.; Critchley, S.; et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 2009, 458, 732–736. [Google Scholar] [CrossRef]
- Reihe, C.A.; Pekas, N.; Wu, P.; Wang, X. Systemic inhibition of neddylation by 3-day MLN4924 treatment regime does not impair autophagic flux in mouse hearts and brains. Am. J. Cardiovasc. Dis. 2017, 7, 134–150. [Google Scholar]
- Yu, H.; Luo, H.; Chang, L.; Wang, S.; Geng, X.; Kang, L.; Zhong, Y.; Cao, Y.; Wang, R.; Yang, X.; et al. The NEDD8-activating enzyme inhibitor MLN4924 reduces ischemic brain injury in mice. Proc. Natl. Acad. Sci. USA 2022, 119, e2111896119. [Google Scholar] [CrossRef]
- Yu, S.; Xie, L.; Liu, Z.; Li, C.; Liang, Y. MLN4924 Exerts a Neuroprotective Effect against Oxidative Stress via Sirt1 in Spinal Cord Ischemia-Reperfusion Injury. Oxid. Med. Cell Longev. 2019, 2019, 7283639. [Google Scholar] [CrossRef] [PubMed]
- Li, Q.; Shen, Y.; Wu, S.; Wei, H.; Zou, J.; Xu, S.; Ling, Q.; Kang, M.; Huang, H.; Chen, X.; et al. MLN4924 Promotes Self-Renewal of Limbal Stem Cells and Ocular Surface Restoration. J. Pers. Med. 2023, 13, 379. [Google Scholar] [CrossRef] [PubMed]
- Gai, W.; Peng, Z.; Liu, C.H.; Zhang, L.; Jiang, H. Advances in Cancer Treatment by Targeting the Neddylation Pathway. Front. Cell Dev. Biol. 2021, 9, 653882. [Google Scholar] [CrossRef]
- Shi, Y.; Inoue, H.; Wu, J.C.; Yamanaka, S. Induced pluripotent stem cell technology: A decade of progress. Nat. Rev. Drug Discov. 2017, 16, 115–130. [Google Scholar] [CrossRef]
- Zhou, H.; Lu, J.; Chinnaswamy, K.; Stuckey, J.A.; Liu, L.; McEachern, D.; Yang, C.Y.; Bernard, D.; Shen, H.; Rui, L.; et al. Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity. Nat. Commun. 2021, 12, 2621. [Google Scholar] [CrossRef]
- Wu, K.; Huynh, K.Q.; Lu, I.; Moustakim, M.; Miao, H.; Yu, C.; Haeusgen, M.J.; Hopkins, B.D.; Huang, L.; Zheng, N.; et al. Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential. Proc. Natl. Acad. Sci. USA 2021, 118, e2007328118. [Google Scholar] [CrossRef]
- Tang, Y.; Moretti, R.; Meiler, J. Recent Advances in Automated Structure-Based De Novo Drug Design. J. Chem. Inf. Model. 2024, 64, 1794–1805. [Google Scholar] [CrossRef]
- Kim, S.H.; Macari, S.; Koller, J.; Chawarska, K. Examining the phenotypic heterogeneity of early autism spectrum disorder: Subtypes and short-term outcomes. J. Child. Psychol. Psychiatry 2016, 57, 93–102. [Google Scholar] [CrossRef]
- Warrier, V.; Zhang, X.; Reed, P.; Havdahl, A.; Moore, T.M.; Cliquet, F.; Leblond, C.S.; Rolland, T.; Rosengren, A.; Rowitch, D.H.; et al. Genetic correlates of phenotypic heterogeneity in autism. Nat. Genet. 2022, 54, 1293–1304. [Google Scholar] [CrossRef]
- Liao, Y.; Sumara, I.; Pangou, E. Non-proteolytic ubiquitylation in cellular signaling and human disease. Commun. Biol. 2022, 5, 114. [Google Scholar] [CrossRef]
- Wang, X.; Tsai, J.W.; LaMonica, B.; Kriegstein, A.R. A new subtype of progenitor cell in the mouse embryonic neocortex. Nat. Neurosci. 2011, 14, 555–561. [Google Scholar] [CrossRef] [PubMed]
- Krienen, F.M.; Goldman, M.; Zhang, Q.; Rosario, C.H.D.R.; Florio, M.; Machold, R.; Saunders, A.; Levandowski, K.; Zaniewski, H.; Schuman, B.; et al. Innovations present in the primate interneuron repertoire. Nature 2020, 586, 262–269. [Google Scholar] [CrossRef] [PubMed]
- Fink, J.J.; Levine, E.S. Uncovering True Cellular Phenotypes: Using Induced Pluripotent Stem Cell-Derived Neurons to Study Early Insults in Neurodevelopmental Disorders. Front. Neurol. 2018, 9, 237. [Google Scholar] [CrossRef]
- Pașca, S.P.; Arlotta, P.; Bateup, H.S.; Camp, J.G.; Cappello, S.; Gage, F.H.; Knoblich, J.A.; Kriegstein, A.R.; Lancaster, M.A.; Ming, G.L.; et al. A framework for neural organoids, assembloids and transplantation studies. Nature 2025, 639, 315–320. [Google Scholar] [CrossRef]
- Fleck, J.S.; Jansen, S.M.J.; Wollny, D.; Zenk, F.; Seimiya, M.; Jain, A.; Okamoto, R.; Santel, M.; He, Z.; Camp, J.G.; et al. Inferring and perturbing cell fate regulomes in human brain organoids. Nature 2023, 621, 365–372. [Google Scholar] [CrossRef]
- Li, C.; Fleck, J.S.; Martins-Costa, C.; Burkard, T.R.; Themann, J.; Stuempflen, M.; Peer, A.M.; Vertesy, Á.; Littleboy, J.B.; Esk, C.; et al. Single-cell brain organoid screening identifies developmental defects in autism. Nature 2023, 621, 373–380. [Google Scholar] [CrossRef]
- Meng, X.; Yao, D.; Imaizumi, K.; Chen, X.; Kelley, K.W.; Reis, N.; Thete, M.V.; Arjun McKinney, A.; Kulkarni, S.; Panagiotakos, G.; et al. Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment. Nature 2023, 622, 359–366. [Google Scholar] [CrossRef]
Target Disrupted | Behavioral Abnormality | Reference | ||||
---|---|---|---|---|---|---|
Gene | Cell Type | Social Interaction | Learning and Memory | Hyperactivity | Anxiety | |
Cul3 | Whole body | ✔ | ✔ | ✔ | (−) | [62,63] |
Cul3 | Neurons and astrocytes | ✔ | (−) | (−) | ✔ | [64] |
Cul3 | DA neurons | N.T. | ✔ | ✔ | (−) | [65] |
Cul4b | Whole body | (−) | ✔ | (−) | (−) | [66] |
Klhl17 | Whole body | ✔ | N.T. | ✔ | (−) | [67] |
Kctd13 | Whole body | (−) | ✔ | (−) | (−) | [68] |
Crbn | Forebrain Glu neurons | N.T. | ✔ | (−) | (−) | [69] |
Cdh1 | Whole body | N.T. | ✔ | N.T. | N.T. | [70] |
Cdh1 | Forebrain Glu neurons | N.T. | ✔ | (−) * | ✔ | [71] |
CRL Scaffold | Substrate Receptor | Substrate | Function | Reference |
---|---|---|---|---|
APC/C | CDH1 | Cyclin B | Promotion of NSC proliferation | [78] |
CUL1 | FBXW7 | Cyclin E | Inhibition of NSC proliferation | [79] |
CUL1 | FBXW7 | NICD | Promotion of NSC differentiation | [80] |
APC/C | CDH1 | CDC25A | Promotion of NSC differentiation | [78] |
APC/C | CDH1 | SKP2 | Promotion of NSC differentiation | [78] |
CUL1 | β-TrCP | β-Catenin | Promotion of NSC differentiation | [82] |
CUL4A | DET1-COP1 | SOX2 | Promotion of NSC differentiation | [83] |
APC/C | CDH1 | SMURF1 | Promotion of dendritogenesis | [99] |
CUL3 | KLHL20 | PDZ-RhoGEF | Inhibition of axon formation | [100] |
CUL3 | KLHL15 | DCX | Inhibition of axon/dendrite complexity | [102] |
CUL4A | CRBN | DCX | Inhibition of axon/dendrite complexity | [103] |
CUL4B | CRBN | DCX | Inhibition of axon/dendrite complexity | [103] |
APC/C | CDH1 | SnoN | Inhibition of axon formation | [104] |
APC/C | CDH1 | ID2 | Inhibition of axon formation | [105] |
CUL4B | (−) * | WDR5 | Promotion of neurite extension | [106] |
CUL5 | SOCS | DAB1 | Inhibition of neuronal migration | [118] |
CUL3 | Unknown | PLS3 | Promotion of neuronal migration | [63] |
APC/C | CDC20 | NeuroD2 | Promotion of presynapse formation | [132] |
CUL1 | FBXL20 | RIM1 | Inhibition of postsynaptic function | [134] |
APC/C | CDH1 | GluA1 | Inhibition of excess synaptic activity | [137] |
APC/C | CDH1 | FMRP1 | Promotion of LTD | [139] |
CUL3 | KCTD13 | GluN1 | Inhibition of excess synaptic activity | [140] |
CUL3 | Unknown | HCN2 | Inhibition of excess synaptic activity | [65] |
CUL7 | FBXW8 | Kv10.1 | Inhibition of potassium current | [146] |
CUL3 | KLHL17 | Unknown | Promotion of synaptic activity | [67] |
APC/C | CDH1 | ROCK2 | Destabilization of dendritic spines | [71] |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Ashitomi, H.; Nakagawa, T.; Nakagawa, M.; Hosoi, T. Cullin-RING Ubiquitin Ligases in Neurodevelopment and Neurodevelopmental Disorders. Biomedicines 2025, 13, 810. https://doi.org/10.3390/biomedicines13040810
Ashitomi H, Nakagawa T, Nakagawa M, Hosoi T. Cullin-RING Ubiquitin Ligases in Neurodevelopment and Neurodevelopmental Disorders. Biomedicines. 2025; 13(4):810. https://doi.org/10.3390/biomedicines13040810
Chicago/Turabian StyleAshitomi, Honoka, Tadashi Nakagawa, Makiko Nakagawa, and Toru Hosoi. 2025. "Cullin-RING Ubiquitin Ligases in Neurodevelopment and Neurodevelopmental Disorders" Biomedicines 13, no. 4: 810. https://doi.org/10.3390/biomedicines13040810
APA StyleAshitomi, H., Nakagawa, T., Nakagawa, M., & Hosoi, T. (2025). Cullin-RING Ubiquitin Ligases in Neurodevelopment and Neurodevelopmental Disorders. Biomedicines, 13(4), 810. https://doi.org/10.3390/biomedicines13040810