SOX2 Regulates Neuronal Differentiation of the Suprachiasmatic Nucleus

Abstract

In mammals, the hypothalamic suprachiasmatic nucleus (SCN) functions as the central circadian pacemaker, orchestrating behavioral and physiological rhythms in alignment to the environmental light/dark cycle. The neurons that comprise the SCN are anatomically and functionally heterogeneous, but despite their physiological importance, little is known about the pathways that guide their specification and differentiation. Here, we report that the stem/progenitor cell transcription factor, Sex determining region Y-box 2 (Sox2), is required in the embryonic SCN to control the expression of SCN-enriched neuropeptides and transcription factors. Ablation of Sox2 in the developing SCN leads to downregulation of circadian neuropeptides as early as embryonic day (E) 15.5, followed by a decrease in the expression of two transcription factors involved in SCN development, Lhx1 and Six6, in neonates. Thymidine analog-retention assays revealed that Sox2 deficiency contributed to reduced survival of SCN neurons during the postnatal period of cell clearance, but did not affect progenitor cell proliferation or SCN specification. Our results identify SOX2 as an essential transcription factor for the proper differentiation and survival of neurons within the developing SCN.

TAU ablation in excitatory neurons and postnatal TAU knockdown reduce epilepsy, SUDEP, and autism behaviors in a Dravet syndrome model

“…Heterozygous Emx1 IRES-cre/+ knockin mice expressing Cre recombinase in excitatory neurons of multiple forebrain regions, including the hippocampus and neocortex ( 54 ), on a homozygous Mapt flox/flox background (ΔTau-EX mice), and heterozygous Vgat IRES-cre/+ mice expressing Cre in inhibitory neurons ( 55 ) on a homozygous Mapt flox/flox background (ΔTau-IN mice) were generated through equivalent breeding schemes, as described in Materials and Methods. During embryonic development, the Emx1 and Vgat promoters initiate gene expression by E12.5 (embryonic day 12.5) ( 54 , 56 , 57 ). Unless indicated otherwise, experimental and control groups in this study included comparable proportions of male and female mice.…”