PITX2 Regulates Procollagen Lysyl Hydroxylase (PLOD) Gene Expression: Implications for the Pathology of Rieger Syndrome

doi:10.1083/jcb.152.3.545

Published online 5 February 2001. doi:10.1083/jcb.152.3.545

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© The Rockefeller University Press, 0021-9525/2001/2/545/ $5.00
The Journal of Cell Biology, Volume 152, Number 3, February 5, 2001 545-552

Original Article

PITX2 Regulates Procollagen Lysyl Hydroxylase (PLOD) Gene Expression: Implications for the Pathology of Rieger Syndrome

Tord A. Hjalt^a, Brad A. Amendt^b, and Jeffrey C. Murray^a
^a Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242
^b Department of Biological Science, University of Tulsa, Tulsa, Oklahoma 74104

Correspondence to: Jeffrey C. Murray, University of Iowa, Department of Pediatrics, 140 EMRB, Iowa City, IA 52242. Tel:(319) 335-6897 Fax:(319) 335-6970 E-mail:jeff-murray{at}uiowa.edu.

The Rieger syndrome is an autosomal dominant disease characterizedby ocular, craniofacial, and umbilical defects. Patients havemutations in PITX2, a paired-bicoid homeobox gene, also involvedin left/right polarity determination. In this study we haveidentified a family of genes for enzymes responsible for hydroxylizinglysines in collagens as one group of likely cognate targetsof PITX2 transcriptional regulation. The mouse procollagen lysylhydroxylase (Plod)-2 gene was enriched for by chromatin precipitationusing a PITX2/Pitx2-specific antibody. Plod-2, as well as thehuman PLOD-1 promoters, contains multiple bicoid (PITX2) bindingelements. We show these elements to bind PITX2 specificallyin vitro. The PLOD-1 promoter induces the expression of a luciferasereporter gene in the presence of PITX2 in cotransfection experiments.The Rieger syndrome causing PITX2 mutant T68P fails to inducePLOD-1–luciferase. Mutations and rearrangements in PLOD-1are known to be prevalent in patients with Ehlers-Danlos syndrome,kyphoscoliosis type (type VI [EDVI]). Several of the same organsystems are involved in Rieger syndrome and EDVI.

Key Words: PITX2, PLOD, Rieger, Ehlers-Danlos, promoter

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