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

Wei Zhang; Yan Li; Sijie Chen; Cuizhen Zhang; Lili Chen; Gang Peng

doi:10.1016/j.jgg.2021.08.019

Volume 49 Issue 3

Mar. 2022

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Article Navigation > Journal of Genetics and Genomics > 2022 > 49(3): 217-229

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

doi: 10.1016/j.jgg.2021.08.019

a State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China;
b Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai 200040, China

Funds:

We thank Dr. J-L Du for the Tg(HuC:GCaMP5H) line. We thank Drs. J.-M. Li, Y. Cao, J. He, and L. Xiao for helpful discussions. We thank L. Gao, X. Li, and C. Han for fish care. This work was 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, and Shanghai Center for Brain Science and Brain-Inspired Technology (Shanghai, China).

Received Date: 2021-05-13
Accepted Date: 2021-08-27
Rev Recd Date: 2021-08-25
Publish Date: 2021-10-01

Abstract

Abstract

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 wild-type 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 neurons. Taken together, our results suggest that nr0b1 regulates neural progenitor proliferation and maintenance to ensure normal hypothalamic neuron development.
- nr0b1,
- DAX-1,
- Hypogonadism,
- Feeding,
- Arcuate nucleus,
- Neural progenitor

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