The transcription factor TCF7L2 functions as a terminal selector in thalamic and habenular regions of the brain

Background: The thalamus and habenula integrate sensory information, adaptive task control, and reward processing. Their postmitotic differentiation is not fully understood, information which is essential for elucidating the aetiology of thalamic and habenular dysfunctions seen in multiple neuropsychiatric disorders. Here, we have used mouse models to investigate the function of the thalamo-habenular-specific transcription factor TCF7L2 in the development and maintaining of this region. Results: In Tcf7l2 knockout embryos, the later developmental expression of the pan-thalamic and pan-habenular selectors Gbx2 and Pou4f1, respectively, was down-regulated, as were subregional transcription factor, cell adhesion and axon guidance genes. Neurons in the thalamo-habenular region did not segregate to form separate nuclei, did not grow axons toward their targets, and their afferent connections were disorganised. Post-developmental knockout of Tcf7l2 mildly affected thalamic patterning. Although generic glutamatergic neurotransmitter identity of the thalamo-habenular domain was properly established and maintained in both mutant mice, numerous region-specific synaptic transmission genes that shape neuronal excitability were down-regulated. Conclusion: TCF7L2 functions as a vertebrate terminal selector, orchestrating a network of transcription factor genes to regulate thalamo-habenular postmitotic molecular differentiation and maintaining terminal differentiation programs.