International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

G7 Cre-Mediated Deletion of the Bmpr Gene Induces CNS Defects and Limb Malformations

Kyung Ahn1, Yuji Mishina2,3, Judy Grinspan4, Richard Behringer2, and E. Bryan Crenshaw III1. 1Dept. of Neuroscience, University of Pennsylvania Medical School, Philadelphia, PA, USA; 2Dept. of Molecular Genetics, MD Anderson Cancer Center, Houston, TX, USA; 3National Institute of Environmental Health Sciences/NIH, Laboratory of Reproductive and Developmental Toxicology, Research Triangle Park, NC, USA; 4Dept. of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA USA

The Bone Morphogenetic Protein Receptor-IA gene (Bmpr) has been hypothesized to play crucial roles throughout mouse development and organogenesis. Targeted deletion of this gene confirms that it plays a crucial role in early embryogenesis (Mishina et al., Genes Dev. 9:3027-3037, 1995). However, the analysis of later embryogenesis is precluded due to the early embryonic lethal phenotype of the knockout. To overcome this problem, we have induced a conditional deletion of a ÒfloxedÓ Bmpr allele. Tissue-specific deletion of the floxed Bmpr allele was induced using a transgenic pedigree containing the promoter region of the POU-domain gene, Brn4/Pou3f4., driving the expression of the cre recombinase gene. This promoter region contains the neural tube-specific enhancers of the Brn4 gene, but not the enhancer regions that direct expression to the inner ear. This promoter fragment has been shown to direct expression throughout much of the neural tube beginning at 8.5 days postcoitus (dpc) in the fore/midbrain, and 9.5 dpc in the spinal cord. We have shown the Brn4/cre pedigree efficiently deletes the Bmpr gene in the brain and spinal cord. Mutant animals often die within 48 hrs of birth with no milk in their stomachs, presumably due to CNS defects. The gross structure of the CNS is unaltered in these animals, and we are currently testing hypotheses regarding Bmpr signaling during CNS development and gliogenesis.

Although the expression of the Brn4 promoter is typically restricted to the neural tube, the Brn4/cre transgenic pedigree used in this study also expressed the cre gene in the apical ectodermal ridge (AER) of the limbs, presumably due to the transgene integration site. AER-specific deletion of the Bmpr gene results in malformations of the limbs. We will report our molecular analysis of this mutant, which address the role of Bmpr signaling during limb development.

 

 


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