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.
Highlights
The proper wiring of the mammalian brain is necessary for cognitive control, including linguistics, motor functions, emotions, memory and associative processing
Upon dissection the cerebral cortex of Snf2h cKO adult mice was visibly smaller than control animals, which is often indicative of a developmental growth defect (Figure 1A and Supplementary Figure 1B)
The cerebellum showed robust expression of Snf2h which is in stark contrast to the Snf2h cKO mouse model generated with the Nestin-Cre driver that showed a dramatic reduction in cerebellar size and lack of Snf2h expression (Supplementary Figures 2, 3A,C) (Alvarez-Saavedra et al, 2014)
Summary
The proper wiring of the mammalian brain is necessary for cognitive control, including linguistics, motor functions, emotions, memory and associative processing. The telencephalon arises from the expansion of a single layer of pseudostratified neuroepithelial cells located in the dorsolateral wall of the ventral neural tube. These cells undergo largely symmetric divisions to expand the progenitor pool and generate the earliest born neurons (Gotz and Huttner, 2005). The RGCs can divide symmetrically or asymmetrically to self-renew, generate projection neurons directly, or produce a committed progenitor known as an intermediate progenitor cell (IPC) (Taverna et al, 2014; Hevner, 2019). The precise mechanisms and involvement of epigenetic regulators remain poorly understood and constitute an intense area of investigation (Greig et al, 2013; Toma and Hanashima, 2015)
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