HESX1- and TCF3-mediated repression of Wnt/β-catenin targets is required for normal development of the anterior forebrain

Abstract

SUMMARYThe Wnt/-catenin pathway plays an essential role during regionalisation of the vertebrate neural plate and its inhibition in the most anterior neural ectoderm is required for normal forebrain development. Hesx1 is a conserved vertebrate-specific transcription factor that is required for forebrain development in Xenopus, mice and humans. Mouse embryos deficient for Hesx1 exhibit a variable degree of forebrain defects, but the molecular mechanisms underlying these defects are not fully understood. Here, we show that injection of a hesx1 morpholino into a 'sensitised' zygotic headless (tcf3) mutant background leads to severe forebrain and eye defects, suggesting an interaction between Hesx1 and the Wnt pathway during zebrafish forebrain development. Consistent with a requirement for Wnt signalling repression, we highlight a synergistic gene dosage-dependent interaction between Hesx1 and Tcf3, a transcriptional repressor of Wnt target genes, to maintain anterior forebrain identity during mouse embryogenesis. In addition, we reveal that Tcf3 is essential within the neural ectoderm to maintain anterior character and that its interaction with Hesx1 ensures the repression of Wnt targets in the developing forebrain. By employing a conditional loss-of-function approach in mouse, we demonstrate that deletion of -catenin, and concomitant reduction of Wnt signalling in the developing anterior forebrain of Hesx1-deficient embryos, leads to a significant rescue of the forebrain defects. Finally, transcriptional profiling of anterior forebrain precursors from mouse embryos expressing eGFP from the Hesx1 locus provides molecular evidence supporting a novel function of Hesx1 in mediating repression of Wnt/-catenin target activation in the developing forebrain.

Transcription factor 7-like 1 is involved in hypothalamo–pituitary axis development in mice and humans

“…S1 A, D, and E). We observed unilateral microphthalmia with no compromise of the telencephalic vesicles in around 20% of the Hesx1 Cre/+ ; Tcf7l1 flox/+ embryos as previously reported (47). Histological and in situ hybridization analyses of Hesx1 Cre/+ ; Tcf7l1 flox/− mutant and control embryos at 17.5 dpc revealed two clearly discernable pituitary phenotypes.…”

“…Previously, we have shown that the cooperation between HESX1 and TCF7L1 is required to repress the activation of the WNT/β-catenin pathway in the anterior neural plate of zebrafish and mouse embryos (47). Our data are in support of the idea that TCF7L1 acts as a repressor during normal pituitary development in mice.…”

“…Tcf7l1 is expressed in the forebrain, including the hypothalamic area, as well as in the anterior pituitary until 14.5 dpc (37). To reveal the function of Tcf7l1 during normal HP axis development, we used the Tcf7l1 flox/flox conditional mouse line (44,47). To generate pituitary-specific Tcf7l1 genetic deletions, Tcf7l1 flox/flox mice were initially Genomes (www.1000genomes.org), Single Nucleotide Polymorphism Database (dbSNP), Exome Variant Server (EVS), and the Exome Aggregation Consortium (ExAC) (comprising >61,000 genomes) Browser (exac.…”

“…TCF7L1 has been shown to play critical roles in maintenance of stem cell pluripotency (42,43), tissue homeostasis of the skin epithelia (44), cell lineage determination during gastrulation (45,46), and brain development in vertebrates (47,48). However, the function of this important transcriptional factor during HP axis development has not been investigated to date.…”

Multi‐genic pattern found in rare type of hypopituitarism: a whole‐exome sequencing study of Han Chinese with pituitary stalk interruption syndrome

“…Among these mutated genes, transcriptional factor HESX1 ‐mediated repression of Wnt/β‐catenin targets is required for the normal development of anterior forebrain 24; Wnt/β‐catenin signalling promotes midbrain dopaminergic progenitor specification, proliferation and neurogenesis by up‐regulating OTX2 in progenitors 25; Notch signalling has been linked to PROP1 expression 26; GPR161 and CDON , the latest mutations found in patients with PSIS by WES recently, are regulators of Shh pathway 27, 28. Collectively, these pathways seem to be critical to pituitary development.…”