Snf2h Drives Chromatin Remodeling to Prime Upper Layer Cortical Neuron Development

Abstract

Alterations in the homeostasis of either cortical progenitor pool, namely the apically located radial glial (RG) cells or the basal intermediate progenitors (IPCs) can severely impair cortical neuron production. Such changes are reflected by microcephaly and are often associated with cognitive defects. Genes encoding epigenetic regulators are a frequent cause of intellectual disability and many have been shown to regulate progenitor cell growth, including our inactivation of the Smarca1 gene encoding Snf2l, which is one of two ISWI mammalian orthologs. Loss of the Snf2l protein resulted in dysregulation of Foxg1 and IPC proliferation leading to macrocephaly. Here we show that inactivation of the closely related Smarca5 gene encoding the Snf2h chromatin remodeler is necessary for embryonic IPC expansion and subsequent specification of callosal projection neurons. Telencephalon-specific Smarca5 cKO embryos have impaired cell cycle kinetics and increased cell death, resulting in fewer Tbr2+ and FoxG1+ IPCs by mid-neurogenesis. These deficits give rise to adult mice with a dramatic reduction in Satb2+ upper layer neurons, and partial agenesis of the corpus callosum. Mice survive into adulthood but molecularly display reduced expression of the clustered protocadherin genes that may further contribute to altered dendritic arborization and a hyperactive behavioral phenotype. Our studies provide novel insight into the developmental function of Snf2h-dependent chromatin remodeling processes during brain development.

Neurodevelopmental Disorders Caused by Defective Chromatin Remodeling: Phenotypic Complexity Is Highlighted by a Review of ATRX Function

“…Indeed, the Atrx Foxg 1 Cre forebrain is reduced in size with a compromised production of upper layer neurons ( Ritchie et al, 2014 ; Huh et al, 2016 ). Similar results have been observed in mice lacking CHD4 and SMARCA5 where the NPCs either fail to progress through the cell cycle or incur significant DNA damage, respectively, prior to undergoing apoptosis ( Alvarez-Saavedra et al, 2014 , 2019 ; Nitarska et al, 2016 ).…”

Pathogenic variants in SMARCA5 , a chromatin remodeler, cause a range of syndromic neurodevelopmental features

“…Such dendritic defects have also been described in cerebellar Purkinje neurons in conditional knockout of Snf2h in mice ( 34 ). In addition, analyses of pan-neuronal knockout and telencephalon-specific knockout of Snf2h in mice have both revealed a smaller brain phenotype ( 34 , 58 ). Apart from its previously reported function in cell proliferation/stem cell self-renewal ( 59 ) and hence smaller head/microcephaly, we identified its requirement in postmitotic neurons.…”

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

“…On the one hand, conditional knockout of Smarca5 in forebrain progenitors ( Emx -cre) resulted in reduced FoxG1 expression, impaired cell cycle kinetics and increased cell death. This resulted in a reduced number of Tbr2 + and FoxG1 + intermediate progenitors and thus a reduced cortical size [ 271 ]. Similarly, conditional knockout of Smarca5 ( Nestin - cre ) caused reduced brain size and cerebral hypoplasia as a result of reduced granular progenitor proliferation [ 266 ].…”

“…Furthermore, knockdown of the chromatin remodeler Chd8 in the neocortex impaired dendrite and axonal growth and branching of upper-layer callosal projection neurons, and resulted in delayed migration of cortical neurons at E18.5, as the majority of labelled cells remained in the VZ/SVZ [ 322 ]. Moreover, mutations in the ISWI complex member Smarca5 cause partial agenesis of the corpus callosum, specifically due to reduced generation of viable upper-layer pyramidal neurons during mid-neurogenesis [ 271 ]. Lastly, a mouse model for Arid1b and Smarcb1 deficits (Coffin-Siris Syndrome) indeed mirror the human phenotype, as Arid1b +/− and Smarcb1 + /inv NesCre + /− mice also have a significantly reduced corpus callosum thickness [ 277 , 282 ].…”