E. Bryan Crenshaw III, Ph.D.

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				E. Bryan Crenshaw III, Ph.D. Mammalian Neurogenetics Lab Center for Childhood Communication Children's Hospital of Philadelphia Adjunct Associate Professor Dept. of Otorhinolaryngology: Head and Neck Surgery Univ of Pennsylvania 712 Abramson Research Center Phone: (267) 426-5240 Fax: (215) 590-5202 email: crenshaw@email.chop.edu Click here for selected publications since Dr. Crenshaw's arrival at Penn RESEARCH INTERESTS Analysis of the role of developmental regulatory factors during mouse neural development. RESEARCH TECHNIQUES Analysis of the role of developmental regulatory factors during mouse neural development. RESEARCH SUMMARY We are interested in using state-of-the-art mouse molecular genetic approaches to characterize neural development. The cell signaling factors, Bone Morphogenetic Proteins (BMPs) and Wnts, play innumerable roles during mammalian development. Howevernfortunately, classical knockouts of genes in these cell signaling pathways result in early embryonic lethality. To overcome this problem, we have generated a conditional knockout approach to study these signaling pathways in the embryonic CNS and limbs. The most widely expressed BMP receptor type IA, Bmpr, which transduces the signals for several BMP ligands, has been conditionally inactivated in the neural tube and somatic ectoderm. This conditional mutant has demonstrated a role for Bmpr signaling in patterning of the neural tube and limb, gliogenesis, subarachnoid space formation (leading to hydrocephaly in these animals), and external genitalia formation. Conditional knockout of the b-catenin gene, a component of the Wnt signaling pathway, demonstrates a role for this gene in regulating cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. To examine the role of BMP signaling during otic development, additional transgenic pedigrees are being developed to conditionally inactivate genes in the embryonic inner ear. Another focus of research in the laboratory examines the role of the POU-homeodomain transcription factor, Brn4/Pou3f4, during inner ear development. Although subtle congenital malformations of the inner ear have a profound affect on human health, little is known about the genetic regulation of the complex ontogeny of this important sensory organ. Using traditional targeted mutagenesis in ES cells, we have demonstrated that mutations in the POU-homeodomain gene Brn4/Pou3f4 result in congenital anomalies of the inner ear. We are further characterizing the role of Brn4 during auditory and vestibular development. Embryonic transgenic mouse demonstrating the expression pattern of the neural enhancer elements in the POU-domain gene, Brn4/Pou3f4. This early midgestation embryo contains a transgene composed of the enhancer elements of the Brn4/Pou34 gene driving the expression of a lacZ reporter gene from a non-specific viral (SV40) promoter. These data demonstrate that a 2.1 kb enhancer region of the Brn4/Pou3f4 gene lying between -3.3 and -1.2 kb upstream of the initiator methionine codon is capable of recapitulating the expression pattern of the endogenous gene in the neural tube.