Page 50 - Mouse Molecular Genetics

Full Abstracts
Program number is above title. Author in bold is the presenter.
Regulation of pancreatic islet lineage decisions. Lori Sussel
James Papizan, Josh Levine. Genetics and Development
Department, Columbia University, New York, NY.
Pancreatic islet cell development and differentiation is coordinately regulated by many well-characterized transcription factors.
Nkx2.2 is a homeodomain-containing regulatory factor required for the appropriate differentiation of pancreatic endocrine cells.
Nkx2.2 null mice lack all insulin-producing beta cells and have reduced numbers of glucagon-producing alpha cells and
pancreatic polypeptide-producing PP cells. In place of these cell types, the mutant islet is populated with cells that produce the
hormone ghrelin. To understand how Nkx2.2 regulates islet cell fate decisions we are exploring the molecular activities of
Nkx2.2 in the developing pancreas. We have generated a series of modified Nkx2.2 alleles that have allowed us to dissect out the
functions of Nkx2.2 during pancreatic development and in the adult. Phenotypic analysis of mice containing different Nkx2.2
mutant alleles demonstrates that Nkx2.2 depends on differential functions and protein interactions to regulate islet cell lineage
specification. Furthermore, Nkx2.2 has unique cell- and time-specific functions to regulate several aspects of beta cell formation,
identity and function. These studies are allowing us to define the complex regulatory activities of Nkx2.2 that are necessary for
specifying and maintaining functional beta cells in the pancreatic islet. Grant support: NIH R01 DK082590 and NIH U01
Regulation of thymus and parathyroid organ fate specification by Shh and Tbx1. Nancy R. Manley
Virginia Bain
Kaitlin Gutierrez
Kim Cardenas
Ellen R. Richie
. 1)
Department of Genetics, University of Georgia, Athens, GA; 2)
Department of Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Science Park Research Division, Smithville,
The thymus and parathyroids perform essential roles in adaptive immunity and calcium homeostasis, respectively. Despite their
discrete functions, both organs develop from shared organ primordia originating from the third pharyngeal pouch endoderm in
mice. These primodria are patterned into two organ domains, indicated by the expression of Foxn1 (thymus) and Gcm2
parathyroid). Although the molecular mechanisms that establish each cell fate are not understood, both the pouch endoderm
itself and the surrounding neural crest cells have been implicated in this process. Our previous studies showed that the Sonic
hedgehog (Shh) null mutation results in loss of parathyroid fate and an expanded thymus domain. As Shh signaling is active in
both the dorsal 3rd pharyngeal pouch endoderm and neighboring neural crest mesenchyme, we ectopically activated or deleted
the Shh signal transducer Smoothened (Smo) in either cell type to determine which cellular target of Shh signaling is the basis for
these patterning defects. Surprisingly, no individual loss or gain of function manipulation recapitulated the Shh null mutant
phenotype, indicating that Shh signaling to either cell type is sufficient to allow establishment of parathyroid fate. Ectopic and
early expression throughout the pouch endoderm of an activated allele of the Shh signal transducer Smoothened (Smo) activated
ectopic Tbx1 expression, but failed to expand Gcm2 expression and parathyroid cell fate. Furthermore, although both Bmp4 and
Foxn1 expression were suppressed in the mid-ventral pouch, these proteins were expressed normally in the most distal pouch,
indicating that these cells were resistant to ectopic expression of activated Smo. Ectopic transgenic expression of Tbx1 itself
further indicated that Tbx1 can suppress the differentiation of thymus-fated cells, but is not sufficient to specify ectopic
parathyroid fate. These data indicate multiple direct and indirect roles for Shh signaling during thymus and parathyroid fate
specification and organogenesis, and identify specific roles for Tbx1 in establishing organ fates within the third pharyngeal
Growth Factor Signaling Pathways in Lung Development and Cancer. David M. Ornitz
Yongjun Yin
Ashley Hill
. 1)
Developmental Biology, Washington University, St. Louis, MO; 2) Children's National Medical Center, Washington DC.
The origins of lung disease often begin during development. Unraveling the complex mechanisms that regulate development is
essential for understanding the pathogenesis of developmental, genetic and acquired lung disease. Lung mesenchyme is a critical
determinant of the shape and size of the lung, the extent and patterning of epithelial branching, the formation of the pulmonary
vasculature and mesenchymal components of the adult lung. Fibroblast Growth Factor 9 (FGF9) is expressed in developing lung
epithelium and mesothelium and has an essential primary role in regulating mesenchymal growth and differentiation through
signaling to mesenchymal FGF receptors (FGFRs) 1 and 2. We have identified a feed-forward regulatory network that involves
mesenchymal FGFRs and Wnt/-catenin signaling. We show that both FGF and Wnt/-catenin function in vivo to regulate
mesenchymal growth and differentiation through a mechanism that involves suppression of Noggin. This finding couples
mesenchymal FGF-Wnt/-catenin signaling with Bmp pathways that regulate epithelial growth and differentiation. Another means
to gain insight into developmental mechanisms is to study the pathogenesis of cancer, a disease which often co-opts embryonic
regulatory mechanisms. A potential link between FGF9 signaling in lung mesenchyme and human lung disease involves the
heritable pediatric lung cancer syndrome, pleuropulmonary blastoma (PPB). PPB is interesting because it arises from embryonic