13-P045 Functional analysis of CHEP12, a novel gene involved in the differentiation of heart precursor cells

The entire central nervous system develops from the neural plate, initially a single-cell layered epithelium. Anterior–posterior patterning is established by signals emanating from tissues outside the neural plate, while local signaling centers that are established within the neural plate itself will refine this initial patterning. One signaling center that plays an important role in the early development of midbrain and anterior hindbrain is the mid/hindbrain organizer (MHB). It is expresses Wnt1 on its rostral side and Fgf8 on its caudal side to exert its effects on future midand hindbrain. We have previously shown that Sip1/Zfhx1b is a multi-domain transcriptional repressor that can interact with several protein partners, thereby exerting several different functions depending on cellular context. We report here a new function of Sip1 in midbrain and hindbrain patterning. At E8.5, Sip1 is expressed in almost the entire neural plate. Sip1 represses Dkk1 expression in the early midbrain, leading to precocious Dkk1 expression at late headfold stage and increased expression at 5S stage in Sip1 knockout embryos. As Dkk1 is an inhibitor of Wnt signaling, the observed aberrant expression of Dkk1 leads to disturbed Wnt–b-catenin signaling in the future midbrain and anterior hindbrain. Hence, this aberrant Wnt signaling in Sip1 knockout embryos leads to early MHB patterning defects, as shown by the altered expression domain of MHB region genes, including En2 and Pax5. Sip1 is thus a regulator of Wnt–b-catenin signaling during early midbrain and anterior hindbrain development and thereby indirectly influences patterning of these tissues.