Developmental Biology Program

Address

The Children’s Hospital of Philadelphia
712 (lab), 707A (office), Abramson Research Center
Philadelphia, PA 19104

Office tel.: 267 426-5240
Fax: 215 590-5202
E-mail: crenshaw@email.chop.edu

Education

Massachusetts Institute of Technology: S.B. (Life Sciences), 1982.

University of California, San Diego: Ph.D (Biology), 1989.

UC San Diego: Postdoctoral Fellow (M.G. Rosenfeld), 1989-1991.

Research Interests

• Analysis of the role of developmental regulatory factors during mouse embryogenesis.

Key words: mammalian embryonic development, BMP receptors, BMPR-IA, POU-domain transcription factors, Cre/loxP conditional gene inactivation, neural development, auditory physiology and function, mouse genetics, knockouts, transgenic mice, animal models of congenital deafness

Search PubMed for articles

Research Techniques

Molecular biology; transgenic mouse and embryonic stem cell technologies; hybridization histochemistry.

Description of Research

We are interested in using state-of-the-art mouse molecular genetic approaches to characterize mammalian development. The cell signaling factors, Bone Morphogenetic Proteins (BMPs) and Wnts, play innumerable roles during mammalian development. However, 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.

Recent Publications

Phippard, D., L. Lu, D. Lee, J.C. Saunders, and E.B. Crenshaw III (1999). Targeted mutagenesis of the POU-domain gene, Brn4/Pou3f4, causes developmental defects in the inner ear. J. Neurosci., 19(14): 5980-5989.

Ahn, K., Y. Mishina, M.C. Hanks, R. Behringer, and E.B. Crenshaw III (2001). BMPR-IA signaling is required for the formation of the apical ectodermal ridge and dorsal/ventral patterning of the limb. Development, 128(22): 4449-4461.

Soshnikova N., D. Zechner, J. Hülsken, R.R. Behringer, M. Taketo, E. B. Crenshaw III, and W. Birchmeier (2003). Genetic interaction between Wnt/b-catenin and BMP receptor signalling during formation of the AER and the dorsal-ventral axis in the limb. Genes Dev., 17: 1963-1968.

Wine-Lee, L., K. Ahn, R.D. Richardson, Y. Mishina, K. Lyon and E.B. Crenshaw III (2004). Signaling through BMP type I receptors is required for development of interneuron cell types in the dorsal spinal cord. Development, 131:5393-5403.

Lab

Rotation Projects

Analysis of mice with targeted mutations using histological and molecular biological techniques. Mutant mouse models currently being analyzed include:

• Tissue-specific mutations in the gene encoding the BMPR-IA receptor using the Cre/loxP system which have malformations of neural tube and inner ear development.
• Knockout of POU-homeodomain gene, Brn4/Pou3f4, which disrupts inner ear development.

Lab personnel:

Kathy Behling, MD-PhD, Postdoctoral Researcher
Lara Wine Lee, MD-PhD Student
Kyung Ahn, Technician
Charles de Charleroy, Technician
Frank Passero, Technician
Hannah Li, Undergraduate Researcher
May Hlaing, Undergraduate Researcher