Research Report 2010 - MDC

Stepwise specification of pancreatic progenitor cells within the endoderm. (A) Schematic modelof the emergence of the pancreatic and hepatic lineage from a common endodermal precursor.(B-D) Prox1-EGFP transgenic (Prox1-EGFP Tg) mouse strains reproduce the endogenous pattern ofProx1 expression in the mouse embryos between embryonic stage (E) 7.5 and 9.5. Arrows indicateProx1 expression in the anterior definitive endoderm (B, B’) and foregut endoderm (C) at E7.5 andE8.5, respectively. (E) Whole-mount in situ hybridization analysis of Pdx1 marks both dorsal andpancreatic buds at E9.5. Abbreviations: Alb, albumin; BP, bipotent precursor; DE, definitive endoderm;Lv, liver; Pa, pancreas; vp, ventral pancreas; dp, dorsal pancreas.intrinsic and extrinsic regulators of this cell fate decisionare under study in my laboratory.Our previous studies have elucidated the molecularevents downstream of the GATA factors within theanterior endoderm in Xenopus laevis. We identifiedGATA downstream targets, such as TGIF2, acting asdevelopmental regulators of the pancreatic versushepatic fate decision. Interestingly, TGIF2 promotes pancreaticfate within the endoderm at the expense ofhepatic markers. Conversely, in TGIF2-depleted embryoswe observed expansion of the hepatic domain at theexpense of pancreatic specification. We are currentlyinvestigating whether TGIF2 controls pancreatic versushepatic fate decision and converts liver to pancreasupon over-expression in mammalian systems.In parallel, we study how and when extrinsic factors,such as BMP, control the emergence of liver versus pancreasfrom the same embryonic region.All together, these experiments will define developmentalregulators that are able not only to specify onefate, but also antagonize the other (eg. pancreatic versushepatic). This knowledge will be crucial for defininglineage reprogramming strategies of liver to pancreastoward a new cure for diabetes.Novel signals guiding endodermal progenitorstoward pancreatic fateKristin Petzold, Heike NaumannIn another line of research, we are investigating molecularplayers that act as instructive factors during earlypancreatic development. In previous studies using theXenopus system, we identified a novel pancreatic factorthat we called Shirin. Very little is known about the biologicalfunction of this protein and, in particular, noembryological function has been assigned to it inmammalian species. We showed that Shirin is specificallyexpressed in the endoderm and pancreatic rudimentsfrom gastrulation onwards, representing one theearliest marker of pancreatic endoderm. Gain-of-functionexperiments in Xenopus indicated that Shirin aloneis sufficient to induce pancreatic identity, acting as apancreatic instructive factor. Similarly, upon conditionalablation of Shirin gene expression in the mouse weobserve defects in pancreas formation. Taken together,our observations suggest a conserved role for Shirin atvery early stages of pancreatic specification.At later developmental stages, Shirin is also expressedin neural crest territory and muscle progenitor cells. Weare currently investigating a potential role of Shirin inthese tissues in collaboration with the group of Prof. C.Birchmeier at the MDC.Selected PublicationsSpagnoli*, FM, Rosa*, A, Brivanlou, AH. (2009). Mesendodermal lineagespecification in embryonic stem cells is under the control of a conservedmicroRNA family. Developmental Cell 16, 517-27. *co-first authorsSpagnoli, FM and Brivanlou, AH. (2008). The Gata5 target, TGIF2, definesthe pancreatic region by modulating BMP signals within the endoderm.Development 135, 451-461.Spagnoli, FM. (2007). From endoderm to pancreas: a multistep journey.The CMLS Journal 64, 2378-2390.Sapkota, G, Alarcón, G, Spagnoli, FM, Brivanlou, AH., Massagué J. (2007).Balancing BMP signaling through integrated inputs into the Smad1linker. Molecular Cell. 25, 441–454.Spagnoli, FM and Brivanlou, AH. (2006). The RNA Binding Protein, Vg1RBP,is Required for Pancreatic Fate Specification. Developmental Biology. 292,442-456.Cardiovascular and Metabolic Disease Research 23