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Article

Multidimensional Functional Profiling of Human Neuropathogenic FOXG1 Alleles in Primary Cultures of Murine Pallial Precursors

1
Cerebral Cortex Development Laboratory, Department of Neuroscience, SISSA, Via Bonomea 265, 34136 Trieste, Italy
2
Neuronal Dynamics Laboratory, Department of Neuroscience, SISSA, Via Bonomea 265, 34136 Trieste, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Current address: Molecular Biology Laboratory, Department of Biology, University of Naples Federico II, Via Cynthia 7, 80126 Naples, Italy.
Academic Editor: Ivano Condò
Int. J. Mol. Sci. 2022, 23(3), 1343; https://doi.org/10.3390/ijms23031343
Received: 30 December 2021 / Revised: 20 January 2022 / Accepted: 21 January 2022 / Published: 25 January 2022
FOXG1 is an ancient transcription factor gene mastering telencephalic development. A number of distinct structural FOXG1 mutations lead to the “FOXG1 syndrome”, a complex and heterogeneous neuropathological entity, for which no cure is presently available. Reconstruction of primary neurodevelopmental/physiological anomalies evoked by these mutations is an obvious pre-requisite for future, precision therapy of such syndrome. Here, as a proof-of-principle, we functionally scored three FOXG1 neuropathogenic alleles, FOXG1G224S, FOXG1W308X, and FOXG1N232S, against their healthy counterpart. Specifically, we delivered transgenes encoding for them to dedicated preparations of murine pallial precursors and quantified their impact on selected neurodevelopmental and physiological processes mastered by Foxg1: pallial stem cell fate choice, proliferation of neural committed progenitors, neuronal architecture, neuronal activity, and their molecular correlates. Briefly, we found that FOXG1G224S and FOXG1W308X generally performed as a gain- and a loss-of-function-allele, respectively, while FOXG1N232S acted as a mild loss-of-function-allele or phenocopied FOXG1WT. These results provide valuable hints about processes misregulated in patients heterozygous for these mutations, to be re-addressed more stringently in patient iPSC-derivative neuro-organoids. Moreover, they suggest that murine pallial cultures may be employed for fast multidimensional profiling of novel, human neuropathogenic FOXG1 alleles, namely a step propedeutic to timely delivery of therapeutic precision treatments. View Full-Text
Keywords: FOXG1 syndrome; functional gene profiling; multidimensional gene profiling; neural fate choice; neural progenitor proliferation; neuron morphology; neuron activity; precision therapy FOXG1 syndrome; functional gene profiling; multidimensional gene profiling; neural fate choice; neural progenitor proliferation; neuron morphology; neuron activity; precision therapy
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MDPI and ACS Style

Frisari, S.; Santo, M.; Hosseini, A.; Manzati, M.; Giugliano, M.; Mallamaci, A. Multidimensional Functional Profiling of Human Neuropathogenic FOXG1 Alleles in Primary Cultures of Murine Pallial Precursors. Int. J. Mol. Sci. 2022, 23, 1343. https://doi.org/10.3390/ijms23031343

AMA Style

Frisari S, Santo M, Hosseini A, Manzati M, Giugliano M, Mallamaci A. Multidimensional Functional Profiling of Human Neuropathogenic FOXG1 Alleles in Primary Cultures of Murine Pallial Precursors. International Journal of Molecular Sciences. 2022; 23(3):1343. https://doi.org/10.3390/ijms23031343

Chicago/Turabian Style

Frisari, Simone, Manuela Santo, Ali Hosseini, Matteo Manzati, Michele Giugliano, and Antonello Mallamaci. 2022. "Multidimensional Functional Profiling of Human Neuropathogenic FOXG1 Alleles in Primary Cultures of Murine Pallial Precursors" International Journal of Molecular Sciences 23, no. 3: 1343. https://doi.org/10.3390/ijms23031343

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