ABOUT
OVERVIEW
Dr. Mishina’s laboratory is interested in functions of BMP signaling during bone development/remodeling and craniofacial development. They recently developed several mouse lines to conditionally decrease or increase levels of BMP signaling using a Cre-loxP system. When BMP signaling through BMP type IA receptor (BMPRIA) was specifically knocked out in osteoblasts, bone mass was increased, unlike what was predicted, by decrease of osteoclastogenesis. Molecular analyses revealed that BMP signaling in osteoblasts positively regulates expression of sclerostin, an inhibitor for Wnt signaling, in turn, negatively regulates Wnt signaling, subsequently influences OPG/RANKL pathway to support osteoclast functions. This would be an interesting model to understand pathogenesis of bone mass related diseases including osteoporosis and Sclerosis. When BMP signaling through BMPRIA was specifically activated in neural crest derived tissues, premature fusion of frontal suture was observed that lead to a morphological abnormality known as craniosinostosis. This phenotype was rescued in a heterozygous null background of Bmpr1a suggesting that amount of BMP signaling needs to be tightly regulated for normal development.Dr. Mishina’s laboratory is interested in functions of BMP signaling during bone development/remodeling and craniofacial development. They recently developed several mouse lines to conditionally decrease or increase levels of BMP signaling using a Cre-loxP system. When BMP signaling through BMP type IA receptor (BMPRIA) was specifically knocked out in osteoblasts, bone mass was increased, unlike what was predicted, by decrease of osteoclastogenesis. Molecular analyses revealed that BMP signaling in osteoblasts positively regulates expression of sclerostin, an inhibitor for Wnt signaling, in turn, negatively regulates Wnt signaling, subsequently influences OPG/RANKL pathway to support osteoclast functions. This would be an interesting model to understand pathogenesis of bone mass related diseases including osteoporosis and Sclerosis. When BMP signaling through BMPRIA was specifically activated in neural crest derived tissues, premature fusion of frontal suture was observed that lead to a morphological abnormality known as craniosinostosis. This phenotype was rescued in a heterozygous null background of Bmpr1a suggesting that amount of BMP signaling needs to be tightly regulated for normal development.
The Molecular Developmental Biology Group uses mouse genetics to study the function of the Bone Morphogenetic Proteins (BMPs) during mouse development.
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.
Figure 1. Strategy for tissue-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.
Figure 2. Osteoblast-specific disruption of Bmpr1a.
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.
Figure 3. Bilateral expression of Pitx2 in Alk2 chimeras.
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
Figure 4. Model for function of ALK2 on left-right patterning.
