Coordination of neural crest cell (NCC) induction and delamination is orchestrated by several transcription factors. Among these, Sry-related HMG box-9 (Sox9) and Snail2 have been implicated in both the induction of NCC identity and, together with phoshorylation, NCC delamination. How phosphorylation effects this function has not been clear. Here we show, in the developing chick neural tube, that phosphorylation of Sox9 on S64 and S181 facilitates its SUMOylation, and the phosphorylated forms of Sox9 are essential for trunk neural crest delamination. Both phosphorylation and to a lesser extent SUMOylation, of Sox9 are required to cooperate with Snail2 to promote delamination. Moreover, bone morphogenetic protein and canonical Wnt signaling induce phosphorylation of Sox9, thereby connecting extracellular signals with the delamination of NCCs. Together the data suggest a model in which extracellular signals initiate phosphorylation of Sox9 and its cooperation with Snail2 to induce NCC delamination.in ovo electroporation | basement membrane N eural crest cells (NCCs) belong to a transient population of embryonic multipotent stem cells that are induced at the interface between the neuroectoderm and the prospective epidermis. These cells delaminate from the epithelium and adopt a characteristic migratory pathway into the periphery, where they contribute to several tissues, notably cranial facial structures and peripheral nervous system (1). During delamination, NCCs undergo an epithelial-mesenchyme transition (EMT), characterized by loss of cell-cell contacts and polarity, as well as acquisition of migratory capabilities (2). Successful EMT and delamination are essential steps for the subsequent migration and differentiation of NCCs. Consequently, mutations in genes involved in NCCs EMT are often associated with congenital defects (3).Previous studies showed that Sry-related HMG box-9 (Sox9), a member of the SoxE family of transcription factors, plays several roles in NC formation, survival, EMT, and differentiation (4-6). In mice harboring a null mutation in Sox9, NCCs were still generated but died by apoptosis before or shortly after NC delamination, suggesting that Sox9 is required for NC survival (4). In chick, misexpression of Sox9 in the neural tube was sufficient to induce NC identity at the expense of neural fate but only inefficiently induced delamination and EMT (5). By contrast, coexpression of Sox9 with the zinc finger-type transcription factor, Snail2, promoted systematic ectopic EMT and NC delamination along the dorsal-ventral extent of the neural tube (4). In addition, in vitro studies showed that Sox9 physically interacts with Snail2 (6). Altogether, these data suggest that the partnership between Sox9 and Snail2 may underlie the ability of Sox9 to induce NC delamination and EMT. However, how the combination of Sox9 and Snail2 achieves this is unclear.The ability of Sox9 to initiate NC delamination appears to be regulated by protein kinase A (PKA)-mediated phosphorylation at two serine residues (S64 a...

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Five children were noted to have arteriohepatic dysplasia (Alagille's syndrome) between 3 and 7 months of age. Prior to diagnosis, four underwent Kasai procedures after intraoperative cholangio‐grams failed to demonstrate patency of the extrahepatic bile ducts. In three patients, a focal proximal hypoplasia of the common hepatic duct was demonstrated with fibrosis and increased vascularity. Hypoplasia of the gallbladder occurred in two patients. Changes were observed in the porta hepatis. Eighty to 208 /tm bile ducts were associated with peripherally located gland‐like structures. These changes are indistinguishable from those in fibrous remnants of extrahepatic biliary atresia. Hepatic features of sequential liver biopsies obtained in the five patients were divided into early and late changes. From birth to 3 months of age, the pathology consisted of cholestasis and bile duct destruction. After 3 months of age, there was persistent cholestasis, paucity of interlobular bile ducts, and portal fibrosis. Ductular proliferation was not an intrinsic change. When present, it was related to a recent episode of cholangitis.