5 with the differentiation

of hepatoblasts into biliary p

5 with the differentiation

of hepatoblasts into biliary precursor cells. The latter form the ductal plate, a single-layered sleeve of cells located around the portal mesenchyme. Around E15.5, tubulogenesis is initiated by the formation of primitive ductal structures (PDS), which are developing ducts asymmetrically lined on the portal side by ductal plate cells, and on the parenchymal side by hepatoblast-like cells. When the PDS mature to ducts (E17.5 to birth), the cells on the portal and parenchymal sides differentiate to mature cholangiocytes, which then symmetrically line the duct lumina; simultaneously, the ducts become integrated in the portal mesenchyme, and the ductal plate cells not involved in tubulogenesis involute.4, 5 For this article, we took advantage of three mouse models with DPMs to investigate the dysmorphogenesis leading STA-9090 concentration to DPM and to study the epistatic relationship between the transcription factors hepatocyte nuclear factor 6 (HNF6) and HNF1β and their downstream targets potentially involved in DPM. Mouse knockouts for HNF6 or with liver-specific inactivation of HNF1β

show DPM associated with cholestasis.6, 7 HNF6 directly stimulates expression buy ZD1839 of HNF1β,6 but the effectors of HNF6 and HNF1β are not known. In pancreatic ducts, HNF6 controls primary cilia formation and stimulates expression of cystin1 (Cys1) and polycystic kidney and hepatic disease-1 (Pkhd1),8 two genes that control ciliogenesis and whose mutations are associated with cyst formation9-14; HNF1β stimulates expression of Pkhd1 in kidneys.15, 16 Moreover, mice deficient in cystin-1 (congenital polycystic kidney [cpk]) display DPMs.17, 18 Thus, we analyze here the dysmorphogenesis causing DPMs in HNF6- and HNF1β-deficient mice, as well as in livers deficient in cystin-1, which is identified as a common target of HNF6 and HNF1β. We focused on differentiation, apicobasal polarity, and ciliogenesis, and found that distinct defects initiated at distinct stages of bile duct morphogenesis may lead to DPMs. ARPKD, autosomal

recessive polycystic kidney disease; cpk, congenital polycystic kidney; DPM, ductal plate malformation; see more E, embryonic day; HNF, hepatocyte nuclear factor; OPN, osteopontin; PDS, primitive ductal structures; PKHD1, polycystic kidney and hepatic disease-1; SOX9, sex-determining region Y–related HMG box transcription factor 9; TβRII, transforming growth factor receptor type II; W, week of gestation; ZO-1, zonula occludens-1. Wild-type, Hnf6, Hnf1bloxP/loxP-Alfp-Cre, and cpk mice6, 7, 19 were treated according to the principles of laboratory animal care of the National Institutes of Health and with approval from institutional animal welfare committees. Tissue samples were obtained in compliance with the French and the Belgian legislations, the 1975 Declaration of Helsinki, and the European Guidelines for the use of human tissues.

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