Congress Abstracts - Society for Developmental Biology

drivers. The Hoxa3 null had unexpected alterations in 3 rd pp patterning and delayed activation of thymus and parathyroid
organogenesis, which later degenerate. Fgf8, Tbx1, and Bmp4, which have been implicated in patterning these organ domains, have
altered expression patterns. Fgf8 (thymus) is expanded and Tbx1 (parathyroid) is reduced, while Bmp4 is missing from the endoderm
but normal in NCCs. Furthermore, organ-specific differentiation markers are expressed a full day later than expected. Neither the
endodermal nor the NCC deletion recapitulates the null phenotype. NCC deletion results in an ectopic thymus and parathyroids due to
separation and migration defects, while the endodermal deletion results in smaller, ectopic organs due to delayed thymus
organogenesis and restricted parathyroid development. These data show that global loss of Hoxa3 does not prevent thymus or
parathyroid organogenesis, but plays a complex role in patterning the 3 rd pp, activating the organ-specific differentiation markers, and
maintaining their development. The Hoxa3 tissue-specific knockouts further show that Hoxa3 in either tissue is sufficient for 3 rd pp
development, but also has tissue-specific functions.
Program/Abstract # 397
Pdx-1 is a determinant of epithelial organization in the developing pancreas
Marty Santos, Leilani M; Cleaver, Ondine (UT-Southwestern Medical Center, USA)
During development the pancreatic epithelium undergoes a transient stratification at a time when the multipotent progenitor cells
(MPCs) that give rise to the exocrine, ductal and endocrine lineages are specified. We hypothesize that this transient stratification is
important for commitment of MPCs to their different lineages, and that defects in the determinants that organize the early pancreatic
epithelium will impact cell fate and differentiation. The transcription factor Pdx-1 is known to be required from the earliest stages of
pancreatic development and later for the specification of endocrine cell fate, particularly that of beta-cells. We have observed that the
timing of failure of the homozygous Pdx-1 null pancreatic bud coincides with the transient stratification of the pancreatic epithelium.
Our findings suggest that Pdx-1 is a positive regulator of the adhesion molecules E-cadherin and beta-catenin, whose expression is
required for normal development and branching of the pancreatic epithelium. In addition, we find that Pdx-1 is required for proper reestablishment
of cell polarity within the de-stratifying epithelium. We observe that levels of laminin are sharply decreased both at the
periphery of the pancreas and within the epithelium. Similarly, apical polarity determinants are reduced within the Pdx1-null stratified
pancreatic epithelium. Together, these defects result in impairment the normal 3D architecture of the pancreas epithelium, suggesting
that basic epithelial adhesion and polarity determinants are targets of Pdx-1. Ultimately, understanding the stepwise processes by
which endocrine beta cells acquire their fate and function will advance efforts towards cell replacement therapies to treat diabetes.
Program/Abstract # 398
Prox1 controls morphogenesis and cell fate in the mouse embryonic liver
Sosa-Pineda, Beatriz; Seth, Asha; Yu, Nanjia; Ye, Jianming; Guez, Fanny; Bedford, David C.; Neale, Geoffrey A. (St. Jude Children's
Research Hospital, USA); Cordi, Sabine (de Duve Institute, Belgium); Brindle, Paul K. (St. Jude Children's Research Hospital, USA);
Lemaigre, Frederic P. (de Duve Institute, Belgium); Kaestner, Klaus H. (University of Pennsylvania, USA)
The function of the liver is central to preserve homeostasis. A better understanding of the cellular and molecular processes establishing
both, its complex architecture and cellular diversity, will help us prevent, diagnose, and cure human hepatic diseases. Here we report
that in mouse embryos the transcription factor Prox1 is expressed in all hepatoblasts of the early hepatic diverticulum (hepatoblasts
being the precursors of both, hepatocytes – the chief epithelial cells in the liver – and cholangiocytes – the epithelial cells lining the
intrahepatic biliary ducts–), in developing hepatocytes, and in emergent intrahepatic bile ducts. We also show that Prox1 is a critical
regulator of liver morphogenesis and hepatic epithelial cell differentiation. Specifically, we determined that Prox1 ablation in mouse
hepatoblasts caused a severe phenotype characterized by formation of aberrant parenchymal epithelial structures covered with a thick
basal membrane, defective bile duct morphogenesis, increased expression of cholangiocyte markers and concomitant reduction of
hepatocyte markers, and widespread fibrosis. These defects were accompanied by decreased expression of specific inhibitors of TGFbeta
signaling. Results of in vitro and in vivo experiments allowed us to conclude that Prox1 limits the responsiveness of hepatoblasts
to TGF-beta signals. In turn, this avoids excessive biliary differentiation, promotes proper bile duct morphogenesis, and prevents
fibrosis. Intriguingly, Prox1 loss-of-function also affected the expression of genes involved in hepatic metabolism, and of microRNAs
regulating biliary development or cell adhesion. Ongoing efforts should address the molecular bases of Prox1 function in developing
hepatic cells.
Program/Abstract # 399
The Septum Transversum Mesenchyme Induces Gall Bladder Development
Saito, Yohei; Kojima, Takuya; Takahashi, Naoki (University of Tokyo, Japan)
The liver, gall bladder, and ventral pancreas are formed from the posterior region of the ventral foregut. During ventral foregutderived
organ development, interactions between the ventral foregut endoderm and the adjacent mesenchyme are critical. For
example, fibroblast growth factor (FGF) from the cardiac mesoderm and bone morphogenetic protein (BMP) from the septum
transversum mesenchyme (STM) induce hepatogenesis. After hepatic induction, Sox17+/Pdx1+ pancreatobiliary common progenitor
cells are present in the remaining posterior portion of the ventral foregut. These progenitor cells differentiate into Sox17+/Pdx1- gall
bladder progenitors, and Sox17-/Pdx1+ ventral pancreatic progenitors, but the cell-extrinsic signals that regulate this differentiation
process are unknown. This study shows that the STM grows in the posterior direction after E8.5 in the mouse, becoming adjacent to
the presumptive gall bladder region to induce gall bladder development. In this induction process, STM-derived BMP4 induces
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