Abstract
SummaryThe transcription factor NKX2-1 is best known for its role in the specification of subsets of cortical, striatal, and pallidal neurons. We demonstrate through genetic fate mapping and intersectional focal septal deletion that NKX2-1 is selectively required in the embryonic septal neuroepithelium for the development of cholinergic septohippocampal projection neurons and large subsets of basal forebrain cholinergic neurons. In the absence of NKX2-1, these neurons fail to develop, causing alterations in hippocampal theta rhythms and severe deficiencies in learning and memory. Our results demonstrate that learning and memory are dependent on NKX2-1 function in the embryonic septum and suggest that cognitive deficiencies that are sometimes associated with pathogenic mutations in NKX2-1 in humans may be a direct consequence of loss of NKX2-1 function.
Highlights
Nkx2-1 is a widely conserved homeobox-encoding ‘‘hub gene’’ with a high degree of connectivity and functional significance during embryogenesis (Kang et al, 2011)
We demonstrate through genetic fate mapping and conditional mutagenesis in mice that NKX2-1 is selectively required for the development of septal cholinergic, but not GABAergic or glutamatergic septohippocampal projection neurons
Given that expression of Nkx2-1 is not restricted to the septum, but extends to the medial ganglionic eminence (MGE) and the preoptic area (POA), we compared this fate map to that of Zic4-Cre;R26R-yellow fluorescent protein (YFP) in order to identify cell types labeled in both mice and derived from the septal NKX2-1 progenitor zone
Summary
Nkx ( known as Ttf, Titf-1, or Tebp) is a widely conserved homeobox-encoding ‘‘hub gene’’ with a high degree of connectivity and functional significance during embryogenesis (Kang et al, 2011). NKX2-1 orchestrates the development of the medial ganglionic eminence (MGE)—one of the main sites of expression of this gene—by repressing alternative neuroepithelial identities and activating MGE-specific transcriptional programs (Butt et al, 2008; Kessaris et al, 2014; Sandberg et al, 2016; Sussel et al, 1999). In the absence of NKX2-1, the MGE becomes respecified into alternative lateral ganglionic eminence (LGE)-like fates and downstream MGE-specific genes, some of which are direct targets of NKX2-1, fail to be activated (Du et al, 2008; Sandberg et al, 2016; Sussel et al, 1999). NKX2-1 constitutes one of the main factors that pattern the ventral forebrain and parcellate its germinal zones into functionally distinct progenitor pools
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