Download Abstract/Session Information for Program Number 1264

Abstract/Session Information for Program Number 1264
Print
Close window
Session Information
Session Title: Gene Structure and Function
Session Type: Poster, Session Location: South Building, 800 Level Hall D/E
Session Time: Wed 1:00PM-8:00PM, Thu 8:00AM-8:00PM, Fri 8:00AM-3:30PM
Abstract Information
Poster Board Number: 1264/T, Presentation Time: Thu Oct. 28 2004 5:00PM-7:00PM
Keywords: KW007 - BONE/JOINT ABNORMALITIES, KW051 - GENES IN DEVELOPMENT, KW105 REGULATION OF TRANSCRIPTION
Abstract Content
Genetic interaction of TRPS1 and RUNX2 during skeletal development identified by SNP analysis of
the RUNX2 promoter. D. Napierala1, R. Morello2, G. Zhou2, Q. Zheng2, T. Bertin2, R. Shivdasani3, B. Lee1,2.
1) HHMI, Baylor College of Medicine, Houston, TX; 2) Department of Molecular and Human Genetics,
Baylor College of Medicine, Houston, TX; 3) Dana-Farber Cancer Institute and Harvard Medical School,
Boston, MA.
TRPS1 and RUNX2 are transcription factors important in skeletal development. Mutations in TRPS1 cause
tricho-rhino-phalangeal syndrome (TRPS), while loss of function mutations of RUNX2 lead to cleidocranial
dysplasia (CCD). Both TRPS and CCD patients exhibit short stature, brachydactyly and cone-shaped
epiphyses suggesting that TRPS1 and RUNX2 may play critical roles during chondrocyte differentiation.
RUNX2 is a master transcriptional regulator of osteoblast differentiation and chondrocyte maturation. Its
expression, however, must be downregulated in mesenchymal condensations during endochondral
ossification. Until now, transcriptional repressors of Runx2 in vivo have yet to be identified. By combining
SNP analysis of control and CCD subjects and cross species sequence analysis, we have identified
conserved GATA domain binding sites in the RUNX2 promoter. Because TRPS1 is the only GATA domain
transcription factor known to function in skeletogenesis, we analyzed its expression pattern during mouse
embryonic development. Interestingly, Trps1 is expressed in skeletal regions where Runx2 needs to be
turned off, including all mesenchymal condensations destined for chondrogenic lineages. Moreover, TRPS1
specifically binds to the GATA cis elements found in the RUNX2 promoter. In transfection studies, Trps1
strongly represses the Runx2 promoter as well as the Runx2 protein ’s transactivation of its target
promoters. Deletion analysis suggests that the interaction is mediated by the RUNT domain. Finally,
transgenic mice overexpressing Trps1 exhibit lengthened growth plates. Together, our data suggest that
Trps1 can inhibit expression of the Runx2 gene as well as Runx2 protein function both early during cell fate
commitment of mesenchymal condensations and later during chondrocyte maturation. This genetic and
biochemical interaction explains some of the clinical features found common in TRPS and CCD.
Print
Close window
The American Society of Human Genetics
9650 Rockville Pike, Bethesda, MD