Postnatal isoform switch and protein localization of LEF1 and TCF7L2 transcription factors in cortical, thalamic, and mesencephalic regions of the adult mouse brain

Abstract

b-Catenin signaling, leading to the activation of lymphoid enhancer-binding factor 1/T cell factor (LEF1/ TCF) transcription factors, plays a well-established role in transcription regulation during development and tissue homeostasis. In the adult organism, the activity of this pathway has been found in stem cell niches and postmitotic thalamic neurons. Recently, studies show that mutations in components of b-catenin signaling networks have been associated with several psychiatric disorders, indicating the involvement of b-catenin and LEF1/TCF proteins in the proper functioning of the brain. Here, we report a comprehensive analysis of LEF1/TCF protein localization and the expression profile of their isoforms in cortical, thalamic, and midbrain regions in mice. We detected LEF1 and TCF7L2 proteins in neurons of the thalamus and dorsal midbrain, i.e., subcortical regions specialized in the integration of diverse sources of sensory information. These neurons also exhibited nuclear localization of b-catenin, suggesting the involvement of b-catenin/LEF1/TCF7L2 in the regulation of gene expression in these regions. Analysis of alternative splicing and promoter usage identified brainspecific TCF7L2 isoforms and revealed a developmentally coordinated transition in the composition of LEF1 and TCF7L2 isoforms. In the case of TCF7L2, the typical brain isoforms lack the so-called C clamp; in addition, the dominant-negative isoforms are predominant in the embryonic thalamus but disappear postnatally. The present study provides a necessary framework to understand the role of LEF1/TCF factors in thalamic and midbrain development until adulthood and predicts that the regulatory role of these proteins in the adult brain is significantly different from their role in the embryonic brain or other non-neural tissues.Keywords b-Catenin Á LEF1 Á TCF7L2 Á Alternative splicing Á Brain Á Thalamus

Murine Joubert syndrome reveals Hedgehog signaling defects as a potential therapeutic target for nephronophthisis

“…2A). Interestingly, in newborn kidney samples, Lef1 is seen as a doublet of two alternative spliced transcripts, which has previously been noted in embryonic murine brain (25). Tcf1 protein expression in newborn kidney was equal, again with alternative splicing evident as has been previously reported in human T cells (26).…”

Wnt/β‐catenin signaling in brain development and mental disorders: keeping TCF7L2 in mind

“…Abundant expression of Tcf7l2 and Lef1 was specifically observed during postmitotic development and in adulthood in the thalamus, habenula, and some midbrain structures in vertebrates, including primates . These TCF7L2‐positive brain regions exhibited massive nuclear β‐catenin accumulation , and high reporter gene activity in Wnt reporter mice .…”

Physiological Role of β-Catenin/TCF Signaling in Neurons of the Adult Brain

“…Unfortunately, to the author’s knowledge, no convincing nuclear immunostaining of β-catenin has been demonstrated in the hippocampus, along the lateral ventricles, or in the olfactory bulbs [49–52]. Yet it should be kept in mind that the sensitivity of immunodetection is limited, and the detection of nuclear β-catenin is particularly challenging because of its abundant amounts at the cell membranes.…”

“…Surprisingly, however, the constant nuclear localization of β-catenin was observed in neurons in subcortical structures that are involved in the integration of sensory information, including the thalamus, epithalamus, pretectum, periaqueductal grey, and superior colliculus [50, 52]. Interestingly, the accumulation of β-catenin was accompanied by high levels of TCF7L2 and LEF1 proteins [52]. LEF1 was also detected in the entorhinal cortex, and TCF7L2 was detected in the inferior colliculus, but β-catenin was not detected in the cellular nuclei in these regions [52].…”

“…Interestingly, the accumulation of β-catenin was accompanied by high levels of TCF7L2 and LEF1 proteins [52]. LEF1 was also detected in the entorhinal cortex, and TCF7L2 was detected in the inferior colliculus, but β-catenin was not detected in the cellular nuclei in these regions [52]. …”