TCF7L2 is a terminal selector that regulates postmitotic differentiation programs and excitability patterns in the thalamus

Abstract The thalamus and habenula integrate sensory information, adaptive task control, and reward processing. Their postmitotic differentiation and establishment of their electrophysiological properties are not well understood. The present study investigated the role of the thalamo-habenular-specific transcription factor TCF7L2 in molecular and functional development of this region. In Tcf7l2 knockout embryos, expression of the postmitotic pan-thalamic and pan-habenular selectors Gbx2 and Pou4f1, respectively, was not maintained, and cell adhesion and axon guidance genes were downregulated. Neurons adopted proper neurotransmitter fate, but they did not segregate to form separate nuclei and did not grow axons toward their targets, and their afferent connections were disorganised. When Tcf7l2 was knocked out postnatally, thalamus-specific voltage-gated ion channel genes were not induced, and burst and tonic spiking in thalamic neurons was strongly reduced. These findings indicate that TCF7L2 functions as a master and versatile terminal selector in the thalamo-habenular region to regulate the morphological differentiation and molecular divergence of cells during embryogenesis and the establishment of postnatal thalamic intrinsic excitability. These results provide new insights into regulatory principles of neuronal terminal differentiation in vertebrates.