Molecular anatomy of the thalamic complex and the underlying transcription factors

Abstract

Thalamocortical loops have been implicated in the control of higher-order cognitive functions, but advances in our understanding of the molecular underpinnings of neocortical organization have not been accompanied by similar analyses in the thalamus. Using expression-based correlation maps and the manual mapping of mouse and human datasets available in the Allen Brain Atlas, we identified a few individual regions and several sets of molecularly related nuclei that partially overlap with the classic grouping that is based on topographical localization and thalamocortical connections. These new molecular divisions of the adult thalamic complex are defined by the combinatorial expression of Tcf7l2, Lef1, Gbx2, Prox1, Pou4f1, Esrrg, and Six3 transcription factor genes. Further in silico and experimental analyses provided the evidence that TCF7L2 might be a pan-thalamic specifier. These results provide substantial insights into the “molecular logic” that underlies organization of the thalamic complex.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-015-1052-5) contains supplementary material, which is available to authorized users.

Potential synergistic action of 19 schizophrenia risk genes in the thalamus

“…This could be important given that each patient might contain a different subset of risk genes that produce dysfunction in different thalamic nuclei. The diversity of gene expression within the thalamus (Nagalski et al, 2016) could lead to the heterogeneity of the symptom set seen among patients. One of the most heterogeneous properties of the thalamus is the density of dopaminergic innervation (Garcia-Cabezas et al, 2009); thus, the synergistic action of genes affecting dopamine hyperfunction may be concentrated in a subset of thalamic nuclei.…”

TCF7L2 regulates postmitotic differentiation programs and excitability patterns in the thalamus

“…Our results do not support this hypothesis, because, in addition to Gbx2 and Pou4f2, subhabenular markers (e.g., Etv1) as well as sub-thalamic markers (e.g., Foxp2, Lef1, Prox1 and Rora) were downregulated in E18.5 Tcf7l2 -/embryos. Rora and Lef1 proved to be direct targets of TCF7L2 in ChIP-seq assay, and our previous in vitro results showed that TCF7L2 can regulate promoters of thalamic factors Gbx2, Pou4f1, Rora and Foxp2, and habenular Nr4a2 and Etv1 (Nagalski et al, 2016).…”

“…TCF7L2 is the only developmentally regulated transcription factor that is expressed throughout prosomere 2 postmitotically (Nagalski et al, 2016). TCF7L2 is not critically involved in the induction of pan-thalamic and pan-habenular identities that are defined by Gbx2 and Pou4f1 expression, respectively, because the expression of these markers was not abolished in Tcf7l2 KO embryos during neurogenesis (E12.5).…”

“…Tcf7l2, a risk gene for schizophrenia and autism (Bem et al, 2019) that encodes a member of the LEF1/TCF transcription factor family (Cadigan and Waterman, 2012), is the only shared marker of prosomere 2 neurons (Nagalski et al, 2013;Nagalski et al, 2016).…”

“…TCF7L2 expression is maintained throughout life and TCF7L2 motifs are overrepresented in putative enhancers of adult thalamus-enriched genes (Nagalski et al, 2016;Wisniewska et al, 2012), suggesting that this factor can be prosomere 2 terminal selector, but its function was tested only during early postmitotic period in zebrafish (Beretta et al, 2013;Husken et al, 2014) and mice (Lee et al, 2017). In Tcf7l2 -/mouse embryos, some markers were misexpressed in the region of prosomere 2, and the formation of axonal tracts was disrupted.…”