Transcriptional regulation of neonatal neural stem cells is a determinant of social behavior

Abstract

Rare gene variants confer a high level of penetrance to neurodevelopmental disorders, but their developmental origin and cellular substrates remain poorly understood. To address this limitation, we explored the role of TBX1, a gene encoded in a rare copy number variant, in cell and mouse models. Here, we report that neonatal Tbx1 deficiency contributes to defective peripubertal social behavior and impairs the proliferation of neonatal neural stem/progenitor cells. Moreover, TBX1 transcriptionally regulates genes linked to post-embryonic neurogenesis and neurodevelopmental disorders associated with other rare gene variants. Our data indicate a precise time window and cell type through which the social dimension is altered by a gene encoded in a rare CNV and provide a potential common mechanistic basis for a group of neurodevelopmental disorders.One-Sentence SummaryTbx1, a gene affecting neonatal stem cell proliferation, influences peripubertal social behavior.

Structural alterations in the amygdala and impaired social incentive learning in a mouse model of a genetic variant associated with neurodevelopmental disorders

“…Embryonic neurogenesis of these regions starts and peaks later than does cortical neurogenesis in neocortical regions in rodents ( 62 , 63 ). Further supporting this possibility, Tbx1 heterozygosity in stem cells initiated during the neonatal period is more effective in negatively impacting a later development of social interaction than that initiated in the same cell population postnatally ( 50 ). Moreover, Tbx1 deficiency alters the embryonic neurogenesis of the primary somatosensory cortex but not that of the motor cortex ( 64 ).…”

“…A coisogenic mouse model of a large 22q11.2 hemizygous deletion is selectively impaired in an amygdaladependent version of fear conditioning (i.e., another cue-dependent task) (71). Tbx1 deficiency alone is sufficient to impair social incentive learning (current study), social interaction (30,50), and neonatal social communication (29,72) in mice. The amygdala is the site of action of another 22q11.2-encoded gene, Sept5, linked to social behavior (73).…”

“…A 3D image of regions with significant effect sizes indicated that cortical volume reductions clustered around the amygdala and that volume increases occurred in the auditory region and its surrounding cortical regions (Fig. 2B Our ChIP-seq (chromatin immunoprecipitation followed by sequencing) data identified TBX1 binding sites near genes relevant to inhibitory neurotransmission, including Gad2, Cep112, Gphn, Nlgn1, 14 Nlgn2, Nlgn3, Nlgn4X, and Nlgn4Y (50). As calretinin (also known as calbindin 2) mRNA colocalizes with a fraction of GABAergic neurons in the rodent amygdala (51) and is enriched in the amygdalopiriform transition zone (52), we evaluated by immunohistochemistry the size of the calretinin-positive neuropil in that region.…”

Structural alterations in the amygdala and impaired social incentive learning in a mouse model of a genetic variant associated with neurodevelopmental disorders

“…A 3D image of regions with significant effect sizes indicated that cortical volume reductions clustered around the amygdala and that volume increases occurred in the auditory region and its surrounding cortical regions (Fig. 2B Our ChIP-seq (chromatin immunoprecipitation followed by sequencing) data identified TBX1 binding sites near genes relevant to inhibitory neurotransmission, including Gad2, Cep112, Gphn, Nlgn1, Nlgn2, Nlgn3, Nlgn4X, and Nlgn4Y (50). As calretinin (also known as calbindin 2) mRNA colocalizes with a fraction of GABAergic neurons in the rodent amygdala (51) and is enriched in the amygdalopiriform transition zone (52), we evaluated by immunohistochemistry the size of the calretinin-positive neuropil in that region.…”