The role of progenitors and neurons in the formation of the subcortical band heterotopia: RhoA mutant as mouse model for understanding the molecular and cellular mechanisms underlying this developmental disorder.
Final Report Abstract
The analysis of RhoA function in the developing cerebral cortex revealed several surprising results in regard to the phenotype observed, the formation of a prominent neuronal heterotopia, as well as in regard to the lack of phenotypes observed, such as the relatively normal migration and process formation of neurons lacking RhoA. While RhoA was apparently largely dispensable in neurons, the lack of RhoA resulted in profound defects in radial glia with defects in adherens junction coupling and apical anchoring as well as defects in process formation or maintenance. Importantly, this cell type specific function of RhoA sheds new light on the etiology of this malformation by affecting the migration scaffold rather than the migrating neurons themselves. Although numerous variants in genes causing structural malformations of human cortical development have been described, modeling their effects in mice inconsistently reproduces these phenotypes. Here we modulated the expression of PLEKHG6, a RhoA activator mutated in a patient with neuronal heterotopia, and demonstrated its role in regulating neural progenitor cell fate via RhoA, and basal progenitor amplification with phenotypic recapitulation of neuronal heterotopia in human brain organoids. With these results we suggest that the RhoA pathway is essential in human cortical development.
Publications
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(2018) A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal Migration. Cell reports 25 (10) 2729-2741.e6
O'Neill, Adam C.; Kyrousi, Christina; Klaus, Johannes; Leventer, Richard J.; Kirk, Edwin P.; Fry, Andrew; Pilz, Daniela T.; Morgan, Tim; Jenkins, Zandra A.; Drukker, Micha; Berkovic, Samuel F.; Scheffer, Ingrid E.; Guerrini, Renzo; Markie, David M.; Götz,
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(2019) Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia. Nature medicine 25 (4) 561–568
Klaus, Johannes; Kanton, Sabina; Kyrousi, Christina; Ayo-Martin, Ane Cristina; Di Giaimo, Rossella; Riesenberg, Stephan; O'Neill, Adam C.; Camp, J. Gray; Tocco, Chiara; Santel, Malgorzata; Rusha, Ejona; Drukker, Micha; Schroeder, Mariana; Götz, Magdalena;
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Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt mammalian neuroprogenitor cell proliferation, differentiation and cerebral cortical development. Nature Genetics 2013, 45(11):1300-1308
Silvia Cappello, Mary J. Gray, Caroline Badouel, Simona Lange, Melanie Einsiedler, Myriam Srour, David Chitayat, Fadi F. Hamdan, Zandra A. Jenkins, Tim Morgan, Nadia Preitner, Tami Uster, Jackie Thomas, Patrick Shannon, Victoria Morrison, Nataliya Di Donato, Lionel Van Maldergem, Teresa Neuhann, Ruth Newbury-Ecob, Marielle Swinkells, Paulien Terhal, Louise C. Wilson, Petra J.G. Zwijnenburg, Andrew J. Sutherland-Smith, Michael A. Black, David Markie, Jacques L. Michaud, Michael A. Simpson, Sahar Mansour, Helen McNeill, Magdalena Götz and Stephen P. Robertson
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Trnp1 regulates expansion and folding of the mammalian cerebral cortex by control of radial glial fate. Cell 2013, 153(3):535-549
Ronny Stahl, Tessa Walcher, Camino De Juan Romero, Gregor Alexander Pilz, Silvia Cappello, Martin Irmler, José Miguel Sanz Anquela, Johannes Beckers, Robert Blum, Victor Borrell and Magdalena Götz
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The role of α-E-catenin in cerebral cortex development: radial glia specific effect on neuronal migration. Frontiers in Neuroscience 2014, 8:215
Marie-Theres Schmid, Franziska Weinandy, Silvia Cappello and Magdalena Götz
