NKX2-1 Is Required in the Embryonic Septum for Cholinergic System Development, Learning, and Memory

The 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.