nr0b1(DAX1) loss of function in zebrafish causes hypothalamic defects via abnormal progenitor proliferation and differentiation

作     者：Wei Zhang Yan Li Sijie Chen Cuizhen Zhang Lili Chen Gang Peng Wei Zhang;Yan Li;Sijie Chen;Cuizhen Zhang;Lili Chen;Gang Peng

作者机构：State Key Laboratory of Medical NeurobiologyMOE Frontiers Center for Brain ScienceInstitutes of Brain ScienceFudan UniversityShanghai 200032China Department of EndocrinologyHuashan HospitalFudan UniversityShanghai 200040China 

出 版 物：《Journal of Genetics and Genomics》 (遗传学报（英文版）)

年 卷 期：2022年第49卷第3期

页      面：217-229页

核心收录：

学科分类：0710[理学-生物学] 07[理学] 071006[理学-神经生物学] 

基　　金：supported by the National Natural Science Foundation of China (31970917) the National Key Research and Development Program of China (2018YFA0801000) the Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01) ZJ Lab Shanghai Center for Brain Science and Brain-Inspired Technology (Shanghai, China) 

主　　题：nr0b1 DAX-1 Hypogonadism Feeding Arcuate nucleus Neural progenitor 

摘      要：The nuclear receptor DAX-1, encoded by the NR0B1 gene, is presented in the hypothalamic tissues in humans and other vertebrates. Human patients with NR0B1 mutations often have hypothalamic-pituitary defects, but the involvement of NR0B1 in hypothalamic development and function is not well understood. Here, we report the disruption of the nr0b1 gene in zebrafish causes abnormal expression of gonadotropins, a reduction in fertilization rate, and an increase in postfasting food intake, which are indicators of abnormal hypothalamic functions. We find that loss of nr0b1 increases the number of prodynorphin(pdyn)-expressing neurons but decreases the number of pro-opiomelanocortin(pomcb)-expressing neurons in the zebrafish hypothalamic arcuate region(ARC). Further examination reveals that the proliferation of progenitor cells is reduced in the hypothalamus of nr0b1 mutant embryos accompanying the decreased expression of genes in the Notch signaling pathway. Additionally, the inhibition of Notch signaling in wildtype embryos increases the number of pdyn neurons, mimicking the nr0b1 mutant phenotype. In contrast,ectopic activation of Notch signaling in nr0b1 mutant embryos decreases the number of pdyn *** together, our results suggest that nr0b1 regulates neural progenitor proliferation and maintenance to ensure normal hypothalamic neuron development.