Journal of Developmental Biology

67 pages, 1229 KB

Open AccessReview

Modeling Complex Developmental Disease: The Case of Polycystic Kidney Disease

by Jay DeLoriea, Cody Casey, Lexee Shearer, Victoria Chen, Angelica Bryant and Chiara Gamberi

J. Dev. Biol. 2026, 14(3), 36; https://doi.org/10.3390/jdb14030036 - 10 Aug 2026

Both genetics and the environment affect the phenotypes of polycystic kidney diseases (PKD), such as autosomal dominant (AD) PKD, autosomal recessive (AR) PKD and nephronophthisis (NPH). Variable phenotypes, pleiotropy, divergent severity and progression, even in family members who inherited the same disease-causing mutation(s), [...] Read more.

Both genetics and the environment affect the phenotypes of polycystic kidney diseases (PKD), such as autosomal dominant (AD) PKD, autosomal recessive (AR) PKD and nephronophthisis (NPH). Variable phenotypes, pleiotropy, divergent severity and progression, even in family members who inherited the same disease-causing mutation(s), signal the involvement of networked genes and modifiers. Several PKD-linked genes function in development and renal tubule morphogenesis. Cystic renal tissues feature metabolic remodeling, functional reprogramming and dysregulation of several shared factors and pathways. ADPKD, ARPKD and NPH partially phenocopy each other. Understanding the developmental arc of cystic kidney disease and its complex phenotypes would improve diagnostics and help develop effective personalized treatments. However, this is challenging to study in vertebrate systems due to genetic redundancy, functional overlap, and a dearth of genetic tools. Underused in this context, Drosophila melanogaster offers high genomic and pathway conservation, a wealth of genetic tools, and rapid generation times, making it a reliable and sustainable model for mechanistic, genome-wide, and precision medicine studies. Here, we surveyed ADPKD, ARPKD, and NPH, compared renal and extrarenal phenotypes, and examined the network of shared and unique contributors, their healthy and diseased functions and conservation from the perspective of mechanistic whole-animal modeling. Full article

18 pages, 23648 KB

Open AccessHypothesis

Speculations on the Evolution of Tail Regeneration in Lizards: Lessons from an Outstanding Case of Organ Regeneration in Amniotes

by Lorenzo Alibardi

J. Dev. Biol. 2026, 14(3), 35; https://doi.org/10.3390/jdb14030035 - 5 Aug 2026

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Abstract

Based on updated information on tail regeneration in lizards, a hypothesis is introduced to explain why these reptiles evolved their regenerative ability. The hypothesis, supported by paleontological evidence, considers tail regeneration associated with autotomy since the Paleozoic in amphibian anthracosaurs of the Carboniferous [...] Read more.

Based on updated information on tail regeneration in lizards, a hypothesis is introduced to explain why these reptiles evolved their regenerative ability. The hypothesis, supported by paleontological evidence, considers tail regeneration associated with autotomy since the Paleozoic in amphibian anthracosaurs of the Carboniferous Period. It is submitted that these ancient amphibians developed tails containing stem cells localized in autotomous planes and/or inter-muscle connective tissues, from which they could regenerate their tails, as some extant salamanders do. The process of stem cell distribution during vertebrate development in salamanders and lizards, however, remains to be demonstrated. It is here suggested that autotomy and regeneration were inherited in the reptiliamorph basal amniotes of the Upper Carboniferous, then in captorhinids of the Permian, in eosuchians of the Triassic, and in the derived Mesozoic lizards, allowing survival and radiation into numerous families. Only in a few lizard families, perhaps under specific ecological adaptations, was autotomy lost, reducing or eliminating tail regeneration. Transcriptome analysis of developing versus regenerating tail indicates numerous differences, suggesting that regeneration utilizes alternative developmental gene pathways from those activated during development. Clarification of gene networks evolved for lizard tail regeneration may indicate the essential steps necessary to regenerate organs also in other amniotes. Full article

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32 pages, 2182 KB

Open AccessReview

Warfarin-Induced Developmental Toxicity: Insights into Embryogenesis, Teratogenicity, and Molecular Pathways

by Evelyn Magee, Grace Kuhnel and Poongodi Geetha-Loganathan

J. Dev. Biol. 2026, 14(3), 34; https://doi.org/10.3390/jdb14030034 - 1 Aug 2026

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Abstract

Warfarin is a coumarin-derived oral anticoagulant widely used for the prevention and treatment of thromboembolic disorders, particularly in patients with mechanical heart valves. The drug exerts its anticoagulant effect by inhibiting vitamin K epoxide reductase, thereby impairing γ-carboxylation of vitamin K-dependent coagulation factors. [...] Read more.

Warfarin is a coumarin-derived oral anticoagulant widely used for the prevention and treatment of thromboembolic disorders, particularly in patients with mechanical heart valves. The drug exerts its anticoagulant effect by inhibiting vitamin K epoxide reductase, thereby impairing γ-carboxylation of vitamin K-dependent coagulation factors. Despite its clinical efficacy, warfarin therapy is associated with a narrow therapeutic index, substantial interindividual variability in dose response, numerous drug interactions, and significant hemorrhagic risk. Maternal warfarin therapy during pregnancy is strongly associated with fetal warfarin syndrome (FWS), a characteristic pattern of embryopathy resulting from in utero exposure to the drug. This review summarizes current knowledge regarding the physicochemical properties, pharmacological mechanisms, dose variability, toxicity, and developmental effects associated with warfarin exposure. Evidence from human clinical studies and vertebrate animal models is discussed to elucidate conserved developmental and molecular mechanisms underlying warfarin teratogenicity. The review also examines the signaling pathways disrupted by warfarin exposure, highlighting that its teratogenic effects extend beyond anticoagulation to the disruption of vitamin K-dependent developmental signaling. Inhibition of γ-glutamyl carboxylation, together with alterations in Gas6/TAM, PXR, Ras, and Wnt/β-catenin signaling pathways, impairs skeletal, vascular, and neural development, contributing to the characteristic abnormalities of fetal warfarin syndrome. Collectively, this review integrates clinical, molecular, and experimental findings to provide a comprehensive understanding of warfarin-induced developmental toxicity. Current knowledge is insufficient to fully elucidate the complex mechanisms underlying warfarin-induced embryopathy and fetal toxicity. Further investigations are warranted to identify safer anticoagulant regimens during pregnancy and to inform the development of novel therapeutic strategies that minimize fetal risk while maintaining maternal anticoagulation. Full article

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16 pages, 5470 KB

Open AccessArticle

Frameshift Mutations in Exon 1 of Fgf10 Frequently Yield Morphologically Normal Embryos

by Khanui Lkhagvadorj, Eiichi Okamura, Toshifumi Morimura, Seiya Mizuno and Masatsugu Ema

J. Dev. Biol. 2026, 14(3), 33; https://doi.org/10.3390/jdb14030033 - 1 Aug 2026

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Abstract

Background/Objectives: CRISPR/Cas9-mediated genome editing enables efficient generation of knockout mouse models; however, frameshift mutations do not always result in complete loss of function. The factors influencing functional inactivation following frameshift mutations remain incompletely understood. Here, we tested whether frameshift-dominant targeting of exon 1 [...] Read more.

Background/Objectives: CRISPR/Cas9-mediated genome editing enables efficient generation of knockout mouse models; however, frameshift mutations do not always result in complete loss of function. The factors influencing functional inactivation following frameshift mutations remain incompletely understood. Here, we tested whether frameshift-dominant targeting of exon 1 is sufficient to generate a null allele of Fgf10, a gene essential for limb formation. Methods: Guide RNAs (gRNAs) were selected using a machine learning-based pipeline to favor microhomology-mediated end joining (MMEJ)-dominant repair. Editing efficiency and indel profiles were assessed via amplicon sequencing in mouse embryonic stem cells (mESCs) and preimplantation embryos. Edited embryos were transferred to surrogate females and analyzed at embryonic day 15.5 (E15.5). Results: Amplicon sequencing confirmed >97% editing efficiency and >80% frameshift alleles in both mESCs and preimplantation embryos, with a predominant 7 bp deletion. Despite highly efficient frameshift-dominant editing, most of the E15.5 embryos were morphologically normal, indicating that exon 1 targeting did not reliably produce null phenotypes. In silico analysis suggested the possible presence of alternative downstream translation initiation sites, and our secretion assay supported this possibility. Initiation from a downstream ATG in a +2 reading frame (e.g., 7 bp deletion) may restore the downstream coding sequence and partially preserve protein function. Conclusions: Frameshift mutations in exon 1 of Fgf10 do not consistently result in functional knockout. The functional outcome depends on the specific reading frame and may be influenced by alternative translation initiation and protein domain architecture. These findings highlight important considerations for designing genome editing strategies to achieve complete gene inactivation. Full article

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22 pages, 71652 KB

Open AccessArticle

Evolutionary Analysis of Vertebrate KCNH Voltage-Gated Potassium Channels and Spatial Expression of kcnh Genes in Zebrafish Embryos

by Kuangyi Wu, Dingxun Wang, Ziyu Dong, Alice Yahui Zhou and GuangJun Zhang

J. Dev. Biol. 2026, 14(3), 32; https://doi.org/10.3390/jdb14030032 - 13 Jul 2026

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Abstract

Voltage-gated potassium channels (Kv) are a large family of potassium channels composed of 40 members across 12 subtypes. The KCNH genes encode three subfamilies of voltage-gated potassium channels: Kv10 (EAG, ether à go go), Kv11 (ERG, EAG-related gene), and Kv12 (ELK, EAG-like [...] Read more.

Voltage-gated potassium channels (Kv) are a large family of potassium channels composed of 40 members across 12 subtypes. The KCNH genes encode three subfamilies of voltage-gated potassium channels: Kv10 (EAG, ether à go go), Kv11 (ERG, EAG-related gene), and Kv12 (ELK, EAG-like K). Kv channels play prominent roles in neuronal and cardiovascular systems. Mutations in Kv channels have been linked to many human diseases, such as epilepsy, heart arrhythmias, and cancers. Significant progress has been made in understanding protein structures, physiological functions, and pharmacological modifiers. However, the evolutionary history and gene expression of vertebrate KCNH genes during embryonic development remain largely unknown. We systematically identified and cloned 14 kcnh genes in zebrafish. Then, we examined the vertebrate KCNH channel evolution by phylogenetic and syntenic analyses. Our data reveal that the three subtypes of the KCNH gene family had already evolved in invertebrates, long before the emergence of vertebrates. The number of vertebrate KCNH genes increased, most likely due to whole-genome duplications (WGDs). In addition, we examined zebrafish kcnh gene expression during early embryogenesis by in situ hybridization. Each subgroup’s genes showed similar but distinct gene expression domains with some exceptions. Most of them were expressed in neural tissues. Notably, kcnh6a showed robust expression in the developing heart, consistent with its conserved role in cardiac repolarization. Additionally, a few kcnh genes were transiently expressed in non-neural tissues, such as somites and the notochord, suggesting they may have a unique role in embryonic development. Our phylogenetic and developmental analyses of KCNH channels shed light on their evolutionary history and potential roles during embryogenesis, in line with their physiological functions and human channelopathies. Full article

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27 pages, 26954 KB

Open AccessArticle

CSF1R+ Macrophages and Osteoclasts Are Essential for Limb Bone Development During Embryogenesis

by Felix Ma, Rose Ru Jing Zhou, Matthew Rosin and Jessica M. Rosin

J. Dev. Biol. 2026, 14(3), 31; https://doi.org/10.3390/jdb14030031 - 8 Jul 2026

Viewed by 454

Abstract

Colony-stimulating factor-1 receptor (CSF1R) provides essential signals for macrophage and osteoclast proliferation, differentiation, and survival, but the roles of CSF1R+ macrophages and osteoclasts during limb morphogenesis are understudied. Here, we utilized a pharmacological model by feeding the CSF1R inhibitor PLX5622 to pregnant mice [...] Read more.

Colony-stimulating factor-1 receptor (CSF1R) provides essential signals for macrophage and osteoclast proliferation, differentiation, and survival, but the roles of CSF1R+ macrophages and osteoclasts during limb morphogenesis are understudied. Here, we utilized a pharmacological model by feeding the CSF1R inhibitor PLX5622 to pregnant mice across gestation to examine how CSF1R disruption impacts embryonic limb development. CSF1R-expressing cells were significantly depleted in response to PLX5622 exposure, including a complete loss of embryonic osteoclasts and osteoclastic activity in the developing limb bones. Although the gross morphology of limb nerves, muscles, cartilage, and bone appeared intact between embryonic day 11.5 (E11.5) and E15.5, prenatal PLX5622 exposure resulted in a completely penetrant truncated phenotype for all postnatal day 1 (P1) limb bones analyzed, suggesting that CSF1R+ cells play important roles in mediating limb bone formation during late embryogenesis. Interestingly, strain-specific defects were observed in the heel, where most of the CD1 mice presented with absent talus and underdeveloped calcaneus bones, while the C57BL/6 mice presented with milder developmental disruptions in both bones. Taken together, our data demonstrate that PLX5622 effectively depletes CSF1R-expressing macrophages and osteoclasts in embryonic limbs and suggest an essential role for embryonic CSF1R+ cells in driving limb bone morphogenesis. Full article

(This article belongs to the Special Issue Mechanisms of Morphogenesis, Degeneration, and Regeneration)

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14 pages, 11304 KB

Open AccessArticle

Valproic Acid Induces Post-Translational Redox Modifications in Mouse Embryos That Are Prevented via Prior Nrf2 Activation

by Aubrey Johansen, Kendall Dunford, Garrett Hasegawa and Jason M. Hansen

J. Dev. Biol. 2026, 14(3), 30; https://doi.org/10.3390/jdb14030030 - 7 Jul 2026

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Abstract

Valproic acid (VPA) is a human developmental toxicant that causes neural tube defects and neurobehavioral deficits. Recent work has implicated VPA-induced oxidative stress in cell models of neurodifferentiation, where oxidative post-translational modifications (PTMs) in undifferentiated cells, primarily protein sulfenylation (Pr-SOH), were unique compared [...] Read more.

Valproic acid (VPA) is a human developmental toxicant that causes neural tube defects and neurobehavioral deficits. Recent work has implicated VPA-induced oxidative stress in cell models of neurodifferentiation, where oxidative post-translational modifications (PTMs) in undifferentiated cells, primarily protein sulfenylation (Pr-SOH), were unique compared to differentiated neurons, primarily protein S-glutathionylation (Pr-SSG). Many of these effects could be mitigated by pretreatments with an Nrf2 inducer. However, it is unclear how early-stage mouse embryos (gestational day 8.5) respond to VPA treatments. Using whole embryo culture, mouse embryos were treated with VPA. A time course assessment of glutathione/glutathione disulfide redox potentials was performed via HPLC throughout 24 h of culture. At 6 h of VPA treatment, embryos were collected for the assessment of protein redox states and specific protein PTMs via various blotting techniques. Also, at 6 h of treatment, the localization of specific PTMs was determined via whole mount staining. Some embryos were pretreated with an Nrf2 inducer. Our data demonstrated that VPA caused a sharp oxidation of redox potentials, which were the greatest between 2 and 6 h, but reverted to control levels by 24 h. Preemptive Nrf2 activation prevented VPA-induced oxidation. Redox blotting showed that VPA caused oxidation of the proteome but this could be reversed by D3T pretreatment. More specifically, Pr-SOH levels increased but Pr-SSG levels were unchanged. Increased Pr-SOH could also be reversed with prior Nrf2 activation. We conclude that embryos at these early stages of development are highly sensitive to VPA and respond more like undifferentiated cells, promoting a more pro-oxidizing outcome for proteins, increasing Pr-SOH formation vs. Pr-SSG. These findings may support specific windows of development where embryos are more susceptible to VPA-induced oxidative injury. Further understanding of redox control and regulation at these susceptible states may serve to develop preventative strategies to reduce poor developmental outcomes after exposures. Full article

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22 pages, 2137 KB

Open AccessReview

Wee Kinases, Big Impact: Wee and Myt Kinases as Critical Regulators of Meiotic Progression

by Shannon Pfeiffer, Lourds M. Fernando, Anna K. Allen and Aimee Jaramillo-Lambert

J. Dev. Biol. 2026, 14(3), 29; https://doi.org/10.3390/jdb14030029 - 1 Jul 2026

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Abstract

Regulation of the cell cycle is critical for maintaining genomic integrity. Therefore, cells have adapted several mechanisms to ensure that cell cycle events occur in a precise order. Some mechanisms regulate cell cycle progression by inhibiting cell cycle drivers, cyclin-dependent kinases (CDKs). The [...] Read more.

Regulation of the cell cycle is critical for maintaining genomic integrity. Therefore, cells have adapted several mechanisms to ensure that cell cycle events occur in a precise order. Some mechanisms regulate cell cycle progression by inhibiting cell cycle drivers, cyclin-dependent kinases (CDKs). The Wee1/Myt1 family of kinases regulate the G2-to-M phase transition by phosphorylating and inactivating Cdk1. Investigations of Wee1/Myt1 have mainly focused on its regulation of mitosis; the role of Wee1/Myt1 kinases in the meiotic cell cycle is less well understood. However, misregulation of Wee1/Myt1 during meiosis can have a range of fertility consequences from mild to severe, including human fertilization failure and infertility. Studies from several organisms reveal that the meiotic functions of Wee1/Myt1 kinases differ from mitosis depending on the species and sex. Here, we review how Wee1/Myt1 kinases regulate cell cycle progression in meiosis across species. We highlight current knowledge of Wee1/Myt1 in meiosis and discuss unanswered questions and new directions to advance the field of meiosis and reproduction. Understanding the molecular and cellular functions of Wee1/Myt1 homologs in these various systems may contribute to the discovery of the mechanisms underlying human infertility cases, better diagnoses, and clinical treatments. Full article

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J. Dev. Biol., Volume 14, Issue 3 (September 2026) – 8 articles

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