Page 74 - Mouse Molecular Genetics

Full Abstracts
Program number is above title. Author in bold is the presenter.
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does not model sporadic tumors and the relative contribution of cells of the tumor and microenvironment has not been well
characterized. We found that expression of a constitutively active form of SMO (SmoM2) in many GCPs at Postnatal (P) day 2
leads to rapid tumor formation before 2 months. Interestingly, while at P8 GCPs throughout the External Granule cell Layer
(
EGL) exhibited over-proliferation, all tumors formed only in the posterior part of the cerebellum. In addition, the tumors had
different cytoarchitectures depending on whether they were located in the hemispheres or the vermis (lateral or medial
cerebellum), suggesting that there are regional differences within the cerebellum with respect to susceptibility to tumor formation
and progression. In order to address the cellular and molecular basis of these observations we are using a new technique called
Mosaic Analysis with Spatial and Temporal control of Recombination (MASTR; Lao, 2012) to alter GLI2 and SMO function in
rare GFP marked GCPs and study the impact on GCP behaviors. In addition, sporadic tumors will be produced in different areas
of the cerebellum for molecular analysis of GFP+ tumor cells. Our studies should provide new insights into the cellular and
genetic mechanisms underlying tumor progression and heterogeneity and to the identification of novel genes (drug targets) to
devise new therapies for HH subtype MBs.
114
Pancreas-specific Deletion of mouse Gata4 and Gata6 Causes Pancreatic Agenesis. Shouhong Xuan
1
,
Matthew Borok
1
,
Kimberly Decker
2
,
Michele Battle
3
,
Stephen Duncan
3
,
Michael Hale
4
,
Raymond MacDonald
4
,
Lori Sussel
1
. 1)
Department of
Genetics & Development, Columbia University, New York, NY 10032; 2) Department of Biochemistry, University of Colorado
Medical School, Aurora, CO 80045, USA; 3) Department of Cell Biology, Neurobiology and Anatomy, Medical College of
Wisconsin, Milwaukee, WI 53226, USA; 4) Department of Molecular Biology, University of Texas Southwestern Medical
Center, Dallas, Texas 75390, USA.
Pancreatic agenesis is a human disorder caused by defects in pancreas development. To date, only a few genes have been linked
to pancreatic agenesis in humans, with mutations in PDX1 and PTF1A reported in only five families with described cases.
Recently, mutations in GATA6 have been identified in a large percentage of human cases and a GATA4 mutant allele has been
implicated in a single case. In the mouse, Gata4 and Gata6 are expressed in several endoderm-derived tissues, including the
pancreas. To analyze the functions of Gata4 and/or Gata6 during mouse pancreatic development, we generated pancreas-specific
deletions of Gata4 and Gata6. Surprisingly, loss of either Gata4 or Gata6 in the pancreas results in only mild pancreatic defects
that are resolved postnatally. However, simultaneous deletion of both Gata4 and Gata6 in the pancreas causes severe pancreatic
agenesis due to the disruption of pancreatic progenitor cell proliferation, defects in branching morphogenesis, and a subsequent
failure to induce the differentiation of progenitor cells expressing Cpa1 and Neurog3. These studies address the conserved and
non-conserved mechanisms underlying Gata4 and Gata6 function during pancreas development and provide a new mouse model
to characterize the underlying developmental defects associated with pancreatic agenesis. We are currently dissecting out the
downstream pathways regulated by Gata factors that mediate pancreatic progenitor cell specification.
Organogenesis
115
Essential role of the Runx2-Cbfb transcription complex for endochondral bone formation.
Na-Rae Park
1
,
Kyung-Eun Lim
1
,
Jeong-Eun Kim
2
,
Ichiro Taniuchi
3
,
Suk-Chul Bae
4
,
Jae-Hwan Jeong
1
,
Je-Yong Choi
1
. 1)
Biochemistry and Cell Biology,
Kyungpook National University, Daegu; 2) Molecular Medicine, Kypook National University, Daegu; 3) Laboratory for
Transcriptional Regulation, RIKEN Research Center for Allergy and Immunology, Kanagawa; 4) Biochemistry, Chungbuk
National University, Cheongju, Republic of Korea.
Core binding factor (Cbf), a partner protein of Runx family transcription factor, has not been determined its function in
cartilage during endochondral bone formation. To explore in vivo function of Cbf in cartilage, we generated cartilage-specifically
deleted Cbf mice (
Cbf
ca/ca
)
crossing with the type II collagen promoter driven Cre mice.
Cbf
ca/+
mice showed no difference in
longevity and skeletal tissues compared with wild type mice.
Cbf
ca/ca
mice resulted in delayed primary ossification center
formation, shorter appendicular skeletons, and immediately death after birth. This phenotype resembled that of Smad1 and
Smad5 double deficient mice. BMP signaling was compromised in Cbf-deficient chondrocytes as evidenced by reduced
expression of BMP target genes like Runx2, Osterix, Osteopontin, and BMP2 as well as reduced phosphorylation of Smad1/5/8.
Deficiency of Cbf in chondrocytes caused rapid proteosomal degradation of Runx2 and reduced chondrocyte maturation with
almost disappearance of hypertrophic chondrocytes. Rescue of Cbf in Cbf-deficient chondrocytes increased Runx2 expression.
Endogenous Runx2-Cbf complex formation and its functional significance provided the first
in vivo
evidence of the essential role
of Cbf during early skeletogenesis. Collectively, these results indicate that Cbf is required for Runx2 stability as a partner protein
in cartilage and the Cbf-Runx2 complex formation plays an important role for endochondral bone formation.
116
Dual embryonic origin of the mouse inner ear. Laina Freyer
1
,
Vimla Aggarwal
2
,
Bernice Morrow
1
. 1)
Genetics, Einstein
College of Medicine, Bronx, NY; 2) Pediatrics, Columbia University Medical Center, New York, NY.