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Molecular Developmental Biology Group

Genetics of Mouse Development

Yuji Mishina, Ph.D.
Yuji Mishina, Ph.D.
Principal Investigator

Tel (919) 541-1095
Fax (919) 541-3800
P.O. Box 12233
Mail Drop C4-10
Research Triangle Park, North Carolina 27709
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Research Summary

The Molecular Developmental Biology Group uses mouse genetics to study the function of the Bone Morphogenetic Proteins (BMPs) during mouse development.

Exon 2 of Bmpr1a was floxed.
Figure 1. Strategy for tissue-specific disruption of Bmpr1a.

One of the most sensitive targets of environmental toxicants is the early stage embryo. Prior to understanding the mechanisms by which environmental toxicants affect the embryos, researchers must first understand the mechanisms which control embryonic development, making the study of concerted gene function very important.

Developmental processes of vertebrate embryos are regulated, at least in part, by secretory molecules such as growth factors. The focus of the studies in the Molecular Developmental Biology group is on the function of BMPs during mouse development. BMPs are members of the Transforming Growth Factor-b (TGF-β) superfamily and were discovered by their ectopic bone-forming ability. However, recent findings demonstrate that BMPs have pleiotropic functions during embryogenesis, ranging from pattern formation to organogenesis. Extensive studies in humans have also revealed that mutations in BMP ligands, receptors and signaling molecules are involved in the pathogenesis of chondrodysplasia, hypertension and tumorigenesis. Members of the group are interested in understanding the roles that BMPs play in three major areas of embryogenesis: mineralized tissues, neural and neural crest-derived tissues, and body plan formation.

The mice that experienced Cre-dependent deletion of Bmpr1a specifically in differentiated osteoblasts were recovered after birth (orange arrows); however, they were smaller than their normal littermates.
Figure 2. Osteoblast-specific disruption of Bmpr1a.

Early embryonic lethality is a problem that group members have encountered in BMP ligand and receptor mutant mice generated by regular gene disruption methods. Because of this problem, the Cre/loxP system was used to produce conditional (tissue-specific) gene mutations. The group’s research approaches should provide valuable insights into how the developmental processes in mineralized tissue, neural tissue and mesodermal tissue involved in body plan formation are regulated by growth factor signaling. The results of these studies may lead to the development of new ways of diagnosing and treating diseases and conditions such as osteoporosis, neural tube defects and failure in body plan pattern formation such as occurs in situs inversus.

Expression of a left-side marker gene, Pitx2, was measured in low contribution chimeras (A, D), high contribution chimeras with wild type ES cells (B, E), and high contribution chimeras with Alk2 mutant ES cells (C, F) at E8.2 (A-C) or at E9.0 (D-F). Blue, Pitx2 expression detected by in situ hybridization; magenta, contribution of ES cells detected by beta-galactosidase activity with Salmon-gal.
Figure 3. Bilateral expression of Pitx2 in Alk2 chimeras.

The underlying hypothesis of the group’s research is that BMP signaling plays a critical role during the formation and maintenance of these tissues and alteration of BMP signaling causes malformation of the tissues. Successful alteration in the function of BMP-related genes—ligands, receptors, signaling molecules and downstream target genes—in a tissue- and stage-specific manner will lead to a greater understanding and a potential cure for diseases or lesions in the tissues of interest.

Major areas of research:

  • Investigating the molecular mechanisms of bone development and bone remodeling
  • Examining the molecular mechanisms of BMP signaling during neural crest cell differentiation and neural tube development
  • Determining the molecular mechanisms of BMP signaling in pattern and axis formation

Current projects:

  • Bone-specific and stage-specific disruption of Bmpr1a. Bmpr1a encodes the type IA receptor for BMP
  • Functional analyses of Dentin matrix protein 1 and Limbin during skeletogenesis
  • Neural crest-specific disruption of Bmpr1a
  • Effect of environmental stress on BMP signaling during neural tissue formation, especially in BMP2 heterozygous and homozygous mutant mice
  • Epiblast-specific gene disruption of Bmpr1a to determine the role of BMPs in gastrulation and patterning of mesoderm
  • Chimeric analyses of the Alk2 gene mutation and epiblast-specific gene disruption of Alk2 to determine the role of BMPs in establishing left-right asymmetry
ALK2 regulates expression of Nodal at the node to establish its asymmetric expression. ALK2 is an essential component needed to initiate Lefty1 expression at the midline for midline barrier function.
Figure 4. Model for function of ALK2 on left-right patterning.

Yuji Mishina, Ph.D., leads the Molecular Developmental Biology Group within the Laboratory of Reproductive and Developmental Toxicology. He received his Ph.D. from the University of Tokyo in Tokyo, Japan. He has published 69 peer-reviewed articles in leading biomedical journals as well as several book chapters. He completed a postdoctoral fellowship at University of Texas, M.D. Anderson Cancer Center before joining NIEHS in 1998.

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Last Reviewed: December 11, 2008