iRhom2 N-末端胞浆区对小鼠乳腺发育的影响及机制研究

iRhom2, which is inactive homologues of the rhomboid intramembrane serine proteases that lack the essential catalytic residues. Although iRhom2 is a pseudoenzymes, but recent researchs shows that iRhom2 exercised important function in living organisms. iRhom2 is required for the release of tumor necrosis factor α (TNFα) in macrophages by controlling the maturation of TNFα-converting enzyme (TACE). iRhom2 regulate the secretion of the epidermal growth factor (EGF) family . Our previous study showed that non-frameshift N-terminal cytoplasmic domain deletion mutation of iRhom2 result in aberrant hair follicle differentiation in iRhom2Uncv mice. Our study demonstrated that N-terminal cytoplasmic domain deletion mutation of iRhom2 is required for the maturation of TACE and mutant iRhom2Uncv is a loss of function mutation. So far, the influence of iRhom2 on mammary gland development is not reported. We accidentally discovered that homozygous female mice loss lactation function in homozygous mice breeding process. Further research results show that in iRhom2Uncv mice exhibit less side-branching. We will study on the effects of N-terminal cytoplasmic domain of iRhom2 in murine mammary gland development. We will research growth regulation of mammary epithelial cells, maintenance, activation and differentiation of mammary stem cell and signaling pathway to elucidate the mechanism of mammary gland development. The project has important theoretical significance on regulation mechanism of mammary gland.

iRhom2属于丧失酶催化活性的膜内菱形样蛋白酶家族成员。iRhom2是假酶，但近年研究表明iRhom2行使重要功能。iRhom2诱导TNFα转化酶(TACE)成熟而促进TNFα释放。另外，iRhom2调节EGF家族分泌。我们前期研究表明iRhom2 N-末端胞浆区缺失突变小鼠（iRhom2Uncv）毛囊分化障碍。iRhom2Uncv影响TACE成熟而阻断NOTCH和WNT信号通路在毛囊的激活。目前，未见iRhom2影响乳腺发育的报道。表型分析发现纯合子iRhom2Uncv雌鼠丧失泌乳功能，形态分析显示该小鼠乳腺导管侧枝发育存在障碍。本项目以iRhom2Uncv小鼠为模型，通过分析iRhom2Uncv小鼠乳腺发育表型，以乳腺上皮细胞生长调控，乳腺干细胞的维持、激活和分化为切入点，结合信号通路分析阐明iRhom2 N–末端对乳腺发育的影响机制。该项目对乳腺发育生长调控机制具有重要意义。