Hey2, also known as hairy and enhancer of split-related with YRPW motif 2, is a basic helix-loop-helix (bHLH) transcriptional repressor. It is involved in multiple biological processes, such as energy metabolism regulation, cell-fate determination during heart development, and the TGF-β/Smad signaling pathway in hepatocellular carcinoma (HCC) [1,2]. Genetic models like gene knockout (KO) and conditional knockout (CKO) mouse models are valuable for studying its functions.

In KO mouse models, Hey2 depletion in adult mouse hearts enhances the expression of mitochondrial oxidation genes and cardiac function, revealing its role in regulating mitochondrial oxidative respiration to maintain cardiac homeostasis [1]. In zebrafish, induced Hey2 expression impairs mitochondrial respiration, leading to cardiomyocyte apoptosis and heart failure [1]. In Hey2 cKO mice generated using Mef2c-AHF-Cre, which affects the anterior part of the second heart field and the right ventricle and outflow tract, there are right-ventricle-specific developmental defects, suggesting Hey2's role in right ventricle development through the Tbx2-Mycn pathway [3]. In HCC cells, knockdown of Hey2 enhances the TGF-β-mediated biological response, indicating its role in interfering with the TGF-β/Smad signaling pathway [2].

In conclusion, Hey2 plays essential roles in regulating energy metabolism in the heart, right ventricle development during cardiac morphogenesis, and the TGF-β/Smad signaling pathway in HCC. Studies using KO and CKO mouse models have significantly contributed to understanding its functions in these disease-related biological processes.

References:

1. She, Peilu, Gao, Bangjun, Li, Dongliang, Zhu, Ping, Zhong, Tao P. 2025. The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis. In Nature communications, 16, 232. doi:10.1038/s41467-024-55557-4. https://pubmed.ncbi.nlm.nih.gov/39747914/

2. Wang, Jianqing, Zhu, Bo, Zhang, Yuanyuan, Sun, Lichun, Xiao, Qianyi. 2019. HEY2 acting as a co-repressor with smad3 and smad4 interferes with the response of TGF-beta in hepatocellular carcinoma. In American journal of translational research, 11, 4367-4381. doi:. https://pubmed.ncbi.nlm.nih.gov/31396342/

3. Seya, Daiki, Ihara, Dai, Shirai, Manabu, Watanabe, Yusuke, Nakagawa, Osamu. 2021. A role of Hey2 transcription factor for right ventricle development through regulation of Tbx2-Mycn pathway during cardiac morphogenesis. In Development, growth & differentiation, 63, 82-92. doi:10.1111/dgd.12707. https://pubmed.ncbi.nlm.nih.gov/33410138/