Loss of Dmrt5 Affects the Formation of the Subplate and Early Corticogenesis

Abstract

Dmrt5 (Dmrta2) and Dmrt3 are key regulators of cortical patterning and progenitor proliferation and differentiation. In this study, we show an altered apical to intermediate progenitor transition, with a delay in SP neurogenesis and premature birth of Ctip2+ cortical neurons in Dmrt5−/− mice. In addition to the cortical progenitors, DMRT5 protein appears present in postmitotic subplate (SP) and marginal zone neurons together with some migrating cortical neurons. We observed the altered split of preplate and the reduced SP and disturbed radial migration of cortical neurons into cortical plate in Dmrt5−/− brains and demonstrated an increase in the proportion of multipolar cells in primary neuronal cultures from Dmrt5−/− embryonic brains. Dmrt5 affects cortical development with specific time sensitivity that we described in two conditional mice with slightly different deletion time. We only observed a transient SP phenotype at E15.5, but not by E18.5 after early (Dmrt5lox/lox;Emx1Cre), but not late (Dmrt5lox/lox;NestinCre) deletion of Dmrt5. SP was less disturbed in Dmrt5lox/lox;Emx1Cre and Dmrt3−/− brains than in Dmrt5−/− and affects dorsomedial cortex more than lateral and caudal cortex. Our study demonstrates a novel function of Dmrt5 in the regulation of early SP formation and radial cortical neuron migration. Summary Statement Our study demonstrates a novel function of Dmrt5 in regulating marginal zone and subplate formation and migration of cortical neurons to cortical plate.

Chromatin remodelerArid1aregulates subplate neuron identity and wiring of cortical connectivity

“…Despite the central position of subplate neurons in orchestrating cortical connectivities, the molecular determinants of subplate wiring function remain largely elusive. Previous studies have focused on genes selectively expressed in subplate neurons Oeschger et al, 2012), which are found to mediate subplate neuron specification, migration, and axon development (Arai et al, 2019;Caviness, 1982;Han et al, 2011;Hevner et al, 2001;Kwan et al, 2008;Lai et al, 2008;Rakic et al, 2006;Ratie et al, 2019;Tiong et al, 2019). Here, by cell type-specific dissection of cortical Arid1a function, we uncover a surprisingly selective role for a ubiquitously-expressed chromatin remodeler in establishing the molecular identity and mediating the non-cell autonomous circuit wiring function of subplate neurons.…”

“…Molecular studies have largely focused on subplate-enriched genes Oeschger et al, 2012). Together, these studies have characterized molecular determinants of subplate neuron specification, migration, and axon development (Arai et al, 2019;Caviness, 1982;Han et al, 2011;Hevner et al, 2001;Kwan et al, 2008;Lai et al, 2008;Rakic et al, 2006;Ratie et al, 2019;Tiong et al, 2019), highlighting the complex genetic regulation required for subplate neuron development. The severe axon misrouting phenotypes of subplate ablation (Ghosh et al, 1990;Shatz, 1992, 1993), however, are not broadly recapitulated in these genetic mutants, precluding further mechanistic investigations into the circuit wiring functions of subplate neurons.…”

“…Despite the central role of SPNs in cortical circuit assembly and their potential contribution to neurodevelopmental disorders (5,23,25), they are relatively understudied compared to their cortical plate counterparts. Previous studies have focused on subplate-enriched genes (24,32) and characterized important molecular determinants of SPN specification, migration, and axon projection (33)(34)(35)(36)(37)(38)(39). The severe axon misrouting phenotypes of subplate ablation (18-20) however, are not broadly recapitulated in these genetic mutants.…”

“…Previous studies have focused on genes selectively expressed in SPNs (24,32). These important studies illuminated the genetic bases of SPN specification, migration, and axon development (33)(34)(35)(36)(37)(38)(39). The severe axon misrouting phenotypes of subplate ablation (18)(19)(20), however, are not broadly recapitulated in these genetic mutants.…”

Chromatin remodeler Arid1a regulates subplate neuron identity and wiring of cortical connectivity

“…Despite the central position of SPNs in orchestrating cortical connectivities, the molecular determinants of SP wiring functions remain largely elusive. Previous studies have focused on genes selectively expressed in SPNs (23,31) and illuminated the genetic bases of SPN specification, migration, and axon development (32)(33)(34)(35)(36)(37)(38). The axon misrouting phenotypes of SP ablation (17)(18)(19), however, are not broadly recapitulated in these genetic mutants.…”