Abstract
Bone morphogenetic proteins (BMPs) play vital roles in regulating stem cell maintenance, differentiation and embryonic development. Intracellularly, BMP signalling is mediated by Smad proteins, which are regulated post-transcriptionally through reversible phosphorylation and ubiquitination. ZC4H2 is a small nuclear protein associated with intellectual disability and neural development in humans. Here, we report that ZC4H2 is highly expressed in the developing neural system and is involved in neural patterning and BMP signalling in Xenopus. Knockdown of ZC4H2 led to expansion of the expression of the pan neural plate marker Sox2 in Xenopus embryos. In mammalian cells, ZC4H2 promotes BMP signalling and is involved in BMP regulated myogenic and osteogenic differentiation of mouse myoblast cells. Mechanistically, ZC4H2 binds and stabilizes Smad1 and Smad5 proteins through reducing their association with the Smurf ubiquitin ligases and thus their ubiquitination. We also found that a group of ZC4H2 mutations, which have been isolated in patients with intellectual disorders, showed weaker Smad-stabilizing activity, suggesting that the ZC4H2–Smad interaction might contribute to proper neural development in humans.
Highlights
Bone morphogenetic proteins (BMPs) belong to the transforming growth factor b (TGFb) superfamily
We found that ZC4H2 was expressed in the animal hemispheres and ectoderm tissues before/in gastrulation and in the neural specific ectoderm when the embryos established their body axes after gastrulation in developing Xenopus embryos
Morpholino-mediated knockdown of ZC4H2 mis-patterned the early ectoderm in Xenopus embryos, which was reproduced in animal caps
Summary
Bone morphogenetic proteins (BMPs) belong to the transforming growth factor b (TGFb) superfamily They are involved in a broad range of cellular responses in metazoa, including cell proliferation, differentiation and embryonic development [1,2,3,4]. Association between ZC4H2 mutation and human intellectual disability syndrome has been reported by two independent studies recently. They both provided evidence that ZC4H2 is expressed in the developing neural system and required for neural development in zebrafish [27,28]. We provide evidence to suggest that the impaired Smads-stabilizing activity of ZC4H2 mutants found in patients with intellectual disability might contribute to the related disease progression
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