Page 76 - Mouse Molecular Genetics

Full Abstracts
Program number is above title. Author in bold is the presenter.
Asxl1) is indentified as an interacting protein of RA receptor (RAR) and functions as either activator or repressor in a cell type-
specific manner. However, the Asxl1 function in vivo remains largely unclear. To determine the physiological function of Asxl1,
we generated Asxl1 heterozygous mice from gene-trap Asxl1 ES cell line. Heterozygotes were viable and fertile. However, most
homozygous Asxl1-null embryos showed severe growth retardation and partial lethality. Even some Asxl1-/- mice were born, all
died shortly after birth with cyanosis, reduced alveolus in the lungs, and respiratory failure. To investigate the cause of neonatal
death, we isolated lung from Asxl1-/- mice and analyzed using physical and histological methods. Asxl1-null lung, compared to
wild-type lung, was floating in PBS. Further histological analysis revealed that Asxl1-/- mice exhibited markedly reduced
alveolar space and thickened alveolar walls associated with undifferentiated alveolar epithelia type 1 cells. Overall, our data
suggest that the Asxl1 is essential for the differentiation of alveolar epithelial cells in mouse lung, which may be critical for air
breathing at birth.
The Role of BMPs in Regulating Digit Number and Identity. Jacqueline L Norrie
Qiang Li
Cortney Bouldin
Steven A Vokes
. 1)
The Section for Molecular, Cellular, and Developmental Biology, The University of Texas at Austin,
Austin, TX; 2) The Department of Molecular Genetics and Microbiology, The University of Florida, Gainesville, Florida.
Bone morphogenetic proteins (BMPs) are essential for bone and cartilage formation. In the vertebrate limb there are 3 partially
redundant BMPs, making it difficult to define their roles in the regulation of limb development. Collective studies suggest that
BMPs play key roles in two phases of limb development. Early in limb development BMPs negatively regulate digit number,
resulting in a pentedactylous limb, and at later timepoints BMPs have been proposed to regulate digit identity. We generated a
mouse model system containing an inducible BMP inhibitor, Gremlin, which we have used to test the role of BMP regulated
processes in the limb. Here we show that in early limb development BMPs negatively digit number. By inhibiting BMPs at
various timepoints we detect a spectrum of polydactylies. In contrast to the prevailing model, our preliminary data suggests that
BMPs inhibition at later timepoints does not lead to a change in digit identity.
The influence of endothelial expression of an Apert syndrome mutation on craniofacial bone development. Christopher
Kazuhiko Kawasaki
Talia Pankratz
Ethylin Jabs
Kenneth Weiss
Joan Richtsmeier
. 1)
Anthropology Dept, Penn
State University, University Park, PA; 2) Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New
York, NY.
A Pro253Arg missense mutation of fibroblast growth factor receptor 2 (FGFR2) is associated with 35% of Apert syndrome
cases. Mice with this mutation display craniofacial dysmorphology similar to affected humans; including coronal suture fusion,
midfacial hypoplasia, and abnormal cranial vault shape. Because tissue interactions are critical for craniofacial development and
FGFR2 is highly pleiotropic, pinpointing the developmental pathways modified to produce this craniofacial dysmorphology is
difficult. Given that Fgfr2 can promote angiogenesis, which is critical for bone development, we crossed Fgfr2(+/P253R) mice
with Tek-cre mice to identify the influence of the P253R mutation when expressed only by endothelial cells. Tek-cre(+/-);
Fgfr2(+/P253R) mice and their littermate controls were sacrificed at P0, P2, and P8. Landmark based morphometric and
individual bone volume based analyses were completed on high resolution computed tomography images of the heads of these
mice in order to quantify cranial bone shape, size, and relative density. Comparisons indicated that Tek-cre(+/-); Fgfr2(+/P253R)
mouse skulls are reduced in overall scale at P0 and P8 with more serious reductions in length and height of the face, vault, and
palate. However, these mice lack the midfacial hypoplasia, coronal craniosynostosis, and extreme rounded vault form of the
Fgfr2+/P253R Apert syndrome mice. Although mean volumes of individual craniofacial bones are generally smaller for the Tek-
cre(+/-); Fgfr2(+/P253R) mice than their littermates, these differences are not significant in two-sample Wilcoxon-tests. Mean
relative densities of individual bones of these mice are slightly lower for some bones at P8, although there is substantial overlap
with the littermates. The results of this study suggest that FGFR2 expression in endothelial cells plays a role in regulating
craniofacial bone dimensions and that expression of the Fgfr2 P253R mutation in endothelial cells contributes to the abnormal
cranial dimensions associated with Apert syndrome. This work was supported in part by a grant from the NSF to CJP (BCS-
and from NIDCR, American Recovery and Reinvestment Act (R01DE018500; 3R01DE018500-02S1) to JTR.
The Planar Cell Polarity Pathway is required in the Second Heart Field lineage for Outflow Tract Morphogenesis. Tanvi
Bing Wang, Jianbo Wang. Department of Cell, Developmental and Integrative Biology, University of Alabama at
Birmingham, Birmingham, AL.
Outflow tract (OFT) malformations underlie a majority of human congenital heart defects. The OFT arises in part from the
Second Heart Field (SHF) progenitors in the pharyngeal and splanchnic mesoderm (SpM), outside of the initial heart. While SHF
proliferation and differentiation have been extensively studied; how these progenitors are deployed to the OFT remains unclear.
Using a set of mouse
Dishevelled2 (Dvl2)
alleles, we demonstrate that the planar cell polarity (PCP) pathway, a branch of the -
catenin independent non-canonical Wnt pathway that regulates cellular polarity and polarized cell behavior during tissue
morphogenesis, is required specifically in the SHF for early OFT morphogenesis and may play a key role in SHF deployment.
We find that mutations in mouse core PCP genes
as well as non-canonical Wnt gene
result in aberrant
cardiac looping. The looping defect is correlated with severe OFT shortening at embryonic day 9.5, characteristic of comprised
contribution from the SHF. Consistent with our genetic interaction studies suggesting that Wnt5a signals through the PCP