TCF7L2 regulates postmitotic differentiation programmes and excitability patterns in the thalamus.

Marcin Andrzej Lipiec,José Luis Ferran,Michał Dąbrowski,Joanna Urban-Ciećko,Chaitali Chakraborty,Angel Toval,Joanna Bem,Kamil Koziński,Łukasz Mateusz Szewczyk,Andrzej Nagalski,Tomasz Zajkowski,Marta Barbara Wiśniewska

doi:10.1242/dev.190181

Abstract

ABSTRACTNeuronal phenotypes are controlled by terminal selector transcription factors in invertebrates, but only a few examples of such regulators have been provided in vertebrates. We hypothesised that TCF7L2 regulates different stages of postmitotic differentiation in the thalamus, and functions as a thalamic terminal selector. To investigate this hypothesis, we used complete and conditional knockouts of Tcf7l2 in mice. The connectivity and clustering of neurons were disrupted in the thalamo-habenular region in Tcf7l2−/− embryos. The expression of subregional thalamic and habenular transcription factors was lost and region-specific cell migration and axon guidance genes were downregulated. In mice with a postnatal Tcf7l2 knockout, the induction of genes that confer thalamic terminal electrophysiological features was impaired. Many of these genes proved to be direct targets of TCF7L2. The role of TCF7L2 in terminal selection was functionally confirmed by impaired firing modes in thalamic neurons in the mutant mice. These data corroborate the existence of master regulators in the vertebrate brain that control stage-specific genetic programmes and regional subroutines, maintain regional transcriptional network during embryonic development, and induce terminal selection postnatally.

Highlights

Studies of invertebrates have shown that terminal differentiation gene batteries in individual classes of neurons are induced and maintained by specific transcription factors that are expressed throughout the life, called terminal selectors (Hobert and Kratsios, 2019)
High TCF7L2 levels were observed in the entire caudal thalamus and medial habenula, and lower levels were in the rostral thalamus and lateral habenula (Fig. 1B)
Little is understood about the way in which the lengthy process of postmitotic differentiation is regulated in the vertebrate brain

Summary

Introduction

Studies of invertebrates have shown that terminal differentiation gene batteries in individual classes of neurons are induced and maintained by specific transcription factors that are expressed throughout the life, called terminal selectors (Hobert and Kratsios, 2019). Regulatory strategies of postmitotic maturation and terminal selection in vertebrates are unclear because only a few terminal selectors have been identified to date (Cho et al, 2014; Flames and Hobert, 2009; Kadkhodaei et al, 2009; Liu et al, 2010; Lodato et al, 2014; Wyler et al, 2016). The habenula controls reward- and aversion-driven behaviours by connecting cortical and subcortical regions with the monoamine system in the brainstem (Benekareddy et al, 2018; Hikosaka, 2010). Thalamic and habenular neurons segregate into discrete nuclei (Shi et al, 2017; Wong et al, 2018), develop variety of subregional identities (Nakagawa, 2019; Phillips et al, 2018), extend axons toward their targets (Hikosaka et al, 2008; López-Bendito, 2018), and acquire electrophysiological characteristics postnatally (Yuge et al, 2011). Knowledge of mechanisms that control postmitotic development in this region is important, because its functional dysconnectivity, which possibly originates from the period of postmitotic maturation, is implicated in schizophrenia, autism and other mental disorders (Browne et al, 2018; Steullet, 2019; Whiting et al, 2018; Woodward et al, 2017)

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Conclusion