Ednrb, the endothelin receptor type B, is a crucial G-protein coupled receptor. It binds to its ligand endothelin 3 (EDN3), and the EDN3/EDNRB signaling pathway is essential in regulating multiple biological processes. This pathway is involved in the development of neural crest-derived lineages, including melanocytes and enteric neurons, and also plays roles in energy metabolism, tumorigenesis, and cell viability regulation [2,3]. Genetic models, such as gene knockout (KO) mouse models, have been instrumental in studying Ednrb's functions.

In KO mouse models, deletion of Ednrb in adipose progenitor cells impairs cold-induced beige adipocyte formation in white adipose tissue (WAT), leading to excessive weight gain, glucose intolerance, and insulin resistance upon high-fat feeding. This reveals its role in promoting the thermogenic differentiation of WAT [1]. In Ednrb -/- mice with Hirschsprung disease, there is a lack of Gad2-expressing enteric neurons in the ganglionated small intestine, which may explain persistent gastrointestinal dysfunction after surgical correction [4]. Also, Ednrb-deficient NC cells show up-regulation of Aim2, and knockdown or knockout of Aim2 can partially rescue the proliferation of Ednrb-deficient melanoblasts, indicating the Ednrb-Aim2-AKT axis in regulating melanocyte development [5].

In conclusion, Ednrb is essential for the development of neural crest-derived lineages, including melanocytes and enteric neurons, and for the thermogenic differentiation of WAT. Mouse KO models have significantly contributed to understanding its role in diseases such as Hirschsprung disease, obesity, and metabolic disorders, providing insights into potential therapeutic strategies for these conditions [1,2,4,5].

References:

1. Wang, Chih-Hao, Tsuji, Tadataka, Wu, Li-Hong, Shamsi, Farnaz, Tseng, Yu-Hua. 2024. Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue. In Nature communications, 15, 7215. doi:10.1038/s41467-024-51579-0. https://pubmed.ncbi.nlm.nih.gov/39174539/

2. McCallion, A S, Chakravarti, A. . EDNRB/EDN3 and Hirschsprung disease type II. In Pigment cell research, 14, 161-9. doi:. https://pubmed.ncbi.nlm.nih.gov/11434563/

3. Bondurand, Nadege, Dufour, Sylvie, Pingault, Veronique. 2018. News from the endothelin-3/EDNRB signaling pathway: Role during enteric nervous system development and involvement in neural crest-associated disorders. In Developmental biology, 444 Suppl 1, S156-S169. doi:10.1016/j.ydbio.2018.08.014. https://pubmed.ncbi.nlm.nih.gov/30171849/

4. Bhave, Sukhada, Guyer, Richard A, Picard, Nicole, Hotta, Ryo, Goldstein, Allan M. 2022. Ednrb -/- mice with hirschsprung disease are missing Gad2-expressing enteric neurons in the ganglionated small intestine. In Frontiers in cell and developmental biology, 10, 917243. doi:10.3389/fcell.2022.917243. https://pubmed.ncbi.nlm.nih.gov/35959491/

5. Chen, Yu, Li, Huirong, Wang, Jing, Rao, Chunbao, Hou, Ling. 2024. The Ednrb-Aim2-AKT axis regulates neural crest-derived melanoblast proliferation during early development. In Development (Cambridge, England), 151, . doi:10.1242/dev.202444. https://pubmed.ncbi.nlm.nih.gov/39555938/