Mice Deficient For TMEFF2Show Growth Retardation And Severe Loss Of White Adipose Tissue

Tmeff2gene encodes a protein with one epidermal growth factor (EGF) likedomain, two follistatin-like domains, a single transmembrane domain, and a shortcytoplasmic tail (also known as tomoregulin2, TPEF and HPP1). Previous studiesreported conflicting functions of Tmeff2. Soluble form of Tmeff2extracellulardomain was shown to promote the survival of dopaminergic neurons and cell growthin HEK293cell line culture. Consistent with the pro-survival role, elevated Tmeff2expression has been associated with androgen-independent prostate cancers. Incontrast, others reported that Tmeff2exhibited anti-proliferative effects onandrogen-independent prostate cancer cell lines. Furthermore, the promoter-region ofTmeff2gene was frequently found to be hypermethylated in many cancers, suggestinga possible role of Tmeff2as a tumor suppressor. Additionally, the tumor suppressoractivity of Tmeff2was thought to depend on its cytoplasmic tail interacting withsarcosine dehydrogenase. The in vivo physiological function of Tmeff2remainselusive.We generated a null allele of Tmeff2gene by replacing the first coding exon ofTmeff2with human placental alkaline phosphatase (hPLAP). Homozygous Tmeff2mutant mice (designated as Tmeff2-KO mice) show growth retardation, fail to gainweight properly, and die around weaning age. No tumors were found in the dyingmutants. AP staining confirmed previous reports that it is widely expressed in thecentral and peripheral nervous system (CNS and PNS). However, despite our besteffort, we did not find any structural or molecular abnormalities of CNS and PNS.Instead, we found that Tmeff2is expressed in the adipocytes, and Tmeff2-KO mice have very little white adipose tissues (WAT), but contain normally developed brownadipose tissues (BAT). Thus, Tmeff2is selectively required in vivo for adipogenesisin WAT but not in BAT.