Ehd4, an Eps15-homology domain-containing protein, is involved in multiple biological processes. It is part of the EHD protein family which regulates endocytic recycling, and also plays a role in specific physiological functions like water homeostasis, cell migration, and flowering time regulation [1,2,3]. Genetic models such as knockout (KO) mice are valuable for studying Ehd4's functions.

In Ehd4-knockout (KO) mice, several phenotypes were observed. Ehd4 -/- mice excreted a higher volume of more dilute urine, suggesting its role in renal water handling. The localization of aquaporin 2 (AQP2) in renal inner medullary principal cells was affected, indicating Ehd4's importance in AQP2 trafficking [1]. In male Ehd4 -/- mice, there was a reduction in testis weight, with increased germ cell apoptosis and other testis-related defects, although high levels of EHD1 in adults could compensate for the lack of EHD4 and prevent severe fertility defects [4]. In endothelial cells, the PACSIN2/EHD4/MICAL-L1 complex controls VE-cadherin trafficking, coordinating endothelial migration and angiogenesis [2]. In rice, ehd4 mutants showed a never-flowering phenotype under natural long-day conditions, revealing its role as a positive regulator of Ehd1 and in photoperiodic control of flowering time [3].

In conclusion, Ehd4 is crucial for maintaining water homeostasis in the body, regulating testicular development in male mice, coordinating endothelial cell behavior during angiogenesis, and controlling photoperiodic flowering in rice. The study of Ehd4 using KO mouse models has provided insights into its functions in these specific biological processes and disease-related areas like water balance and testicular development [1,2,3,4].

References:

1. Rahman, Shamma S, Moffitt, Alexandra E J, Trease, Andrew J, Band, Hamid, Boesen, Erika I. 2017. EHD4 is a novel regulator of urinary water homeostasis. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 31, 5217-5233. doi:10.1096/fj.201601182RR. https://pubmed.ncbi.nlm.nih.gov/28778975/

2. Malinova, Tsveta S, Angulo-Urarte, Ana, Nüchel, Julian, Plomann, Markus, Huveneers, Stephan. 2021. A junctional PACSIN2/EHD4/MICAL-L1 complex coordinates VE-cadherin trafficking for endothelial migration and angiogenesis. In Nature communications, 12, 2610. doi:10.1038/s41467-021-22873-y. https://pubmed.ncbi.nlm.nih.gov/33972531/

3. Gao, He, Zheng, Xiao-Ming, Fei, Guilin, Wang, Haiyang, Wan, Jian-Min. 2013. Ehd4 encodes a novel and Oryza-genus-specific regulator of photoperiodic flowering in rice. In PLoS genetics, 9, e1003281. doi:10.1371/journal.pgen.1003281. https://pubmed.ncbi.nlm.nih.gov/23437005/

4. George, Manju, Rainey, Mark A, Naramura, Mayumi, Band, Vimla, Band, Hamid. . Ehd4 is required to attain normal prepubertal testis size but dispensable for fertility in male mice. In Genesis (New York, N.Y. : 2000), 48, 328-42. doi:10.1002/dvg.20620. https://pubmed.ncbi.nlm.nih.gov/20213691/