ΔNp63 Regulates HTRA4 Expression During Extravillous Trophoblast Differentiation

Abstract

During early placentation, trophoblast cell columns help anchor the developing embryo into the uterine wall. Although proximally continuous with villous cytotrophoblast (CTB), distally these cells differentiate into invasive extravillous trophoblast (EVT). In the absence of normal EVT differentiation, pregnancies can terminate early or be complicated by fetal growth restriction. We previously reported that ΔNp63, a p53 family member, is highly expressed in CTB but is lost when these cells further differentiate into EVT. We now further explore the downstream targets of p63 during EVT differentiation using both primary CTB and the JEG3 human trophoblast. Using gene microarrays, we identified HTRA4 as one such p63 target: HTRA4 is a member of the high temperature requirement A family of serine proteases, and have been shown to regulate trophoblast fusogenic activity and invasion. p63‐overexpressing JEG3 cells showed decreased expression of HTRA4, and decreased cell migration; conversely, down‐regulation of p63 increased HTRA4 expression and restored cell migration. In primary human trophoblast, isolated from early placental tissues, we found that HTRA4 is expressed at low levels in p63‐high EGFR+/HLAG‐ CTBs, and at high levels in p63‐low EGFR‐/HLAG+ EVTs. Taken together, these data indicate that EVT differentiation is accompanied by loss of p63 and gain of HTRA4. Our data reveal a potentially novel p63‐HTRA4 axis, involved in trophoblast migration and invasion.