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
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
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 development and limb formation.
- Knockout of POU-homeodomain gene, Brn4/Pou3f4, which disrupts inner ear development.
Kathy Behling, MD, PhD, Postdoctoral Researcher
Kyung Ahn, Technician
Frank Passero, Technician
May Hlaing, Undergraduate Researcher
Hannah Li, Undergraduate Researcher
- Assistant Professor of Neuroscience at University of Pennsylvania School of Medicine (1994 – 2002)
- Assistant Professor of Otorhinolaryngology: Head and Neck Surgery at University of Pennsylvania School of Medicine (2000 – 2001)
- Adjunct Associate Professor of Otorhinolaryngology: Head and Neck Surgery at University of Pennsylvania School of Medicine (2003– present)
- Ph.D., Biology, University of California at San Diego (1989)
- S.B., Life Sciences, Massachusetts Institute of Technology (1982)
- Liu W, Oh SH, Kang YK, Li G, Doan TM, Little M, Li L, Ahn K, Crenshaw III, EB, Frenz DA. Bone morphogenetic protein 4 (BMP4): Regulator of capsule chondrogenesis in the developing mouse inner ear. Developmental Dynamics. Vol 226. 2003:427-438.
- Zechner D, Fujita Y, Julsken J, Walther I, Taketo MM, Crenshaw III, EB, Birchmeier W, Birchmeier C. beta-Catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. Developmental Biology. Vol 258. 2003:406-418.
- Soshnikova N, Zechner D, Hülsken J, Behringer RR, Taketo M, Crenshaw III, EB, Birchmeier W. Genetic interaction between Wnt/b-catenin and BMP receptor signaling during formation of the AER and the dorsal-ventral axis in the limb. Genes & Development. Vol 17. 2003:1963-1968.
- Suzuki K, Bachiller D, Chen YP, Kamikawa M, Ogi H, Haraguchi R, Ogino Y, Mishina Y, Ahn K, Crenshaw III, EB, Yamada G. Regulation of outgrowth and apoptosis for the terminal appendage, external genitalia, development by concerted functions of BMP signaling. Development. Vol 130. 2003:6209-6220.
- Andl T, Ahn K, Kairo A, Croft NJ, Cebra-Thomas JA, Lyons KM, Mishina Y, Crenshaw III, EB, Millar SE. Epithelial Bmpr1a regulates proliferation and differentiation in postnatal hair follicles and is essential for tooth development. Development. Vol 131. 2004:2257-2268.
- Heller RS, Stoffers DA, Liu A, Schedl A, Crenshaw III, EB, Madsen OD, Serup P. The role of Brn4 / Pou3f4 and Pax6 in forming the pancreatic glucagon cell identity. Developmental Biology. Vol 268. 2004:123-134.
- Ahn K, Soshnikova N, Zechner D, Huelsken J, Mishina Y, Behringer RR, Taketo MM, Birchmeier W, Crenshaw III, EB. Genetic interactions between BMP receptor and Wnt/beta-catenin signaling during formation of the AER and the dorsal-ventral axis in the limb. Abstracts of the Mid-Atlantic Regional Meeting, (Society for Developmental Biology). (7) . 2003:25.