F-box protein FBXO30 mediates retinoic acid receptor \u03b3 ubiquitination and regulates BMP signaling in neural tube defects

Xiyue Cheng,Xiaolu Xie,Qin Zhang,Ting Zhang,Jianxin Wu,Dan Li,Shan Wang,Pei Pei,Juan Yu

doi:10.1038/s41419-019-1783-y

Abstract

Retinoic acid (RA), an active derivative of vitamin A, is critical for the neural system development. During the neural development, the RA/RA receptor (RAR) pathway suppresses BMP signaling-mediated proliferation and differentiation of neural progenitor cells. However, how the stability of RAR is regulated during neural system development and how BMP pathway genes expression in neural tissue from human fetuses affected with neural tube defects (NTDs) remain elusive. Here, we report that FBXO30 acts as an E3 ubiquitin ligase and targets RARγ for ubiquitination and proteasomal degradation. In this way, FBXO30 positively regulates BMP signaling in mammalian cells. Moreover, RA treatment leads to suppression of BMP signaling by reducing the level of FBXO30 in mammalian cells and in mouse embryos with NTDs. In samples from human NTDs with high levels of retinol, downregulation of BMP target genes was observed, along with aberrant FBXO30 levels. Collectively, our results demonstrate that RARγ levels are controlled by FBXO30-mediated ubiquitination and that FBXO30 is a key regulator of BMP signaling. Furthermore, we suggest a novel mechanism by which high-retinol levels affect the level of FBXO30, which antagonizes BMP signaling during early stage development.

Highlights

The vertebrate neural tube is the precursor to the central nervous system (CNS)
Our study reveals that the ubiquitin protein ligase, F-box domain-containing protein 30 (FBXO30), negatively regulates the stability of RARγ protein, and functions to regulate bone morphogenic protein (BMP) signaling
By comparing libraries from control and FBXO30-depleted cells, we identified a significant number of differentially expressed genes, including 86 upregulated and 78 downregulated genes in FBXO30-depleted cells; (Fig. 1b; S3 and S4 Tables)

Summary

Introduction

The vertebrate neural tube is the precursor to the central nervous system (CNS). Neural tube defects (NTDs) are a group of birth defects caused by incomplete neural tube closure during embryonic development[1,2]. Failure to complete closure of the craniofacial region leads to exencephaly, and if the exposed brain tissue is degraded it appears as anencephaly, which usually causes embryonic lethality[3,4]. NTDs are caused by the external environment and genetic factors. Imbalance of nutrient intake (e.g., folate or vitamin A) during peripregnancy is an RA causes many of the same embryonic developmental defects seen with vitamin A deficiency, which is why vitamin A intake levels should be monitored carefully during pregnancy[14]. Official journal of the Cell Death Differentiation Association

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