Disruption of the signaling pathways that control chondrocyte maturation in the growth plate can result in dwarfism. PTHrP is a key negative regulator of chondrocyte maturation, whose expression is first observed in the periarticular perichondrium and subsequently in round proliferative chondrocytes in the growth plate. PTHrP expression is itself dependent upon Ihh expression in prehypertrophic chondrocytes in the growth plate. Because PTHrP expression is dependent upon Ihh signaling, factors that act to either increase or decrease Ihh signaling in the growth plate could potentially have a profound effect on both the expression of PTHrP and the rate of chondrocyte hypertrophy. Recent work in my lab has indicated that the transcription factor GATA6 is a negative regulator of Sonic Hedgehog (Shh) signaling in the limb bud, and may play a similar role in the growth plate as a negative regulator of Indian Hedgehog (Ihh) signaling. Consistent with this latter notion, we have found that deletion of GATA6 from all chondrocytes in Col2-Cre;GATA6flox/flox mice results in both dwarfism and delayed chondrocyte maturation. These findings suggest that loss of GATA6 in chondrocytes may disregulate the Ihh/PTHrP signaling loop, which would result in defects in the regulation of normal chondrocyte maturation. In addition to GATA6, TRPS1 which is mutated in Tricho-rhino-phalangeal syndrome (TRPS) is another transcription factor containing a GATA factor-like DNA binding domain that is expressed in the growth plate. Patients with TRPS have short stature, hip abnormalities, cone- shaped epiphyses and premature closure of growth plates reflecting defects in endochondral ossification. In addition, mutation of TPRS1 in mice leads to delayed chondrocyte hypertrophy in the growth plate.
The aims of this proposal seek to shed new light on the transcriptional regulation of chondrocyte hypertrophy, by determining both how GATA6 acts to promote chondrocyte maturation in the growth plate and determine whether GATA6 and TPRS1 share overlapping roles in promoting growth plate maturation.

Public Health Relevance

The goals of this project are to determine how GATA6 promotes proper regulation of chondrocyte maturation in the growth plate and acts to prevent the development of postnatal dwarfism in the adult. Achieving these goals will significantly broaden our knowledge of the genes and regulatory circuitry that are necessary for the proper growth and maturation of chondrocytes in the growth plate.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR060735-01A1
Application #
8435770
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Tyree, Bernadette
Project Start
2013-03-01
Project End
2018-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$359,834
Indirect Cost
$147,334
Name
Harvard University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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Kozhemyakina, Elena; Ionescu, Andreia; Lassar, Andrew B (2014) GATA6 is a crucial regulator of Shh in the limb bud. PLoS Genet 10:e1004072
Daoud, Georges; Kempf, Hervé; Kumar, Deepak et al. (2014) BMP-mediated induction of GATA4/5/6 blocks somitic responsiveness to SHH. Development 141:3978-87
Kumar, Deepak; Lassar, Andrew B (2014) Fibroblast growth factor maintains chondrogenic potential of limb bud mesenchymal cells by modulating DNMT3A recruitment. Cell Rep 8:1419-31