The role of polycystic kidney disease 1 (Pkd1) in craniofacial skeletal development and response to mechanical stress
By: by Bo Hou
Published: 2008
Language: eng
Number of pages: 143
Description: Mechanical stress is an important factor in modulating postnatal skeletal growth and development. To study the cellular responses that lead to functional adaptation in the craniofacial skeleton, a mouse midpalatal suture expansion model was developed and subsequent cellular and tissue responses were characterized. An expansive force across the midpalatal suture resulted in increased periosteal cell proliferation and differentiation into osteoblasts throughout the experimental period. As a result, new bone formation was observed in the expanded suture area. This model system has proven to be very efficient in studying the cellular behaviors leading to bone modeling/remodeling in response to mechanical stress. It has also allowed hypotheses of mechanotransduction in the craniofacial skeleton to be tested using genetically modified mouse strains. Polycystin 1 (Pkd1) has recently been proposed as mechanosensor in kidney epithelial cells in response to fluid flow. In this thesis, mice with targeted inactivation of Pkd1 in skeletal tissues were generated and analyzed. Pkd1-deficient mice exhibited a delay in intramembranous ossification of the skull, retarded postnatal growth of the craniofacial complex and premature closure of cranial base synchondroses due to significantly decreased proliferation of osteochondroprogenitor cells. These results have demonstrated, for the first time, that PC1 is an essential regulator of postnatal growth of the craniofacial skeleton.

To investigate the role of PC1 in mechanotransduction in skeletal tissues, midpalatal suture expansion was studied in Pkd1-deficient mice. The mutant mice exhibit a significantly reduced osteogenic response to tensional stress due to reduced proliferation, delayed differentiation and increased apoptosis of osteochondroprogenitor cells. Furthermore, nasal cartilage of Pkd1-deficient mice undergoes unusual postnatal endochondral ossification and this process is accelerated upon application of expansive force across the midpalatal suture. Taken together, the results suggest that PC1 plays a critical role in the response of osteochondroprogenitor cells to mechanical stress. To our knowledge, this is the first study to demonstrate that PC1 is involved in mechanotransduction in non-renal tissue. More importantly, the strategy of combining in vivo mechanical models such as midpalatal suture expansion with conditional knockout mice has laid the foundation for future studies to explore mechanisms underlying mechanotransduction in the craniofacial skeleton.
Notes: "May 2008."

Thesis (Ph.D., Dept. of Developmental Biology)--Harvard University, 2008.

Includes bibliographical references.