HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (14) Citing Articles via Google Scholar Google Scholar Articles by Diehl, A. G. Articles by Gage, P. J. Search for Related Content PubMed PubMed Citation Articles by Diehl, A. G. Articles by Gage, P. J.

Extraocular Muscle Morphogenesis and Gene Expression Are Regulated by Pitx2 Gene Dose

¹From the Departments of Ophthalmology and Visual Sciences, and ³Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan.

PURPOSE. PITX2 gene dose plays a central role in Axenfeld-Rieger syndrome. The purpose of this study was to test the hypothesis that the effects of Pitx2 gene dose on eye development can be molecularly dissected in available Pitx2 mutant mice.

METHODS. A panel of mice with Pitx2 gene dose ranging from wild-type (+/+) to none (–/–) was generated. Eye morphogenesis was assessed in animals with each Pitx2 gene dose. We also compared global gene expression in eye primordia taken from e12.5 Pitx2^+/+, Pitx2^+/–, Pitx2^–/– embryos using gene microarrays. The validity of microarray results was confirmed by qRT-PCR.

RESULTS. Morphogenesis of all extraocular muscle bundles correlated highly with Pitx2 gene dose, but there were some differences in sensitivity among muscle groups. Superior and inferior oblique muscles were most sensitive and disappeared before the four rectus muscles. Expression of muscle-specific genes was globally sensitive to Pitx2 gene dose, including the muscle-specific transcription factor genes Myf5, Myog, Myod1, Smyd1, Msc, and Csrp3.

CONCLUSIONS. Pitx2 gene dose regulates both morphogenesis and gene expression in developing extraocular muscles. The expression of key muscle-specific transcription factor genes is regulated by Pitx2 gene dose, suggesting that sufficient levels of PITX2 protein are essential for early initiation of the myogenic regulatory cascade in extraocular muscles. These results document the first ocular tissue affected by Pitx2 gene dose in a model organism, where the underlying mechanisms can be analyzed, and provide a paradigm for future experiments designed to elucidate additional effects of Pitx2 gene dose during eye development.

This article has been cited by other articles:

				J. Weng, J. Luo, X. Cheng, C. Jin, X. Zhou, J. Qu, L. Tu, D. Ai, D. Li, J. Wang, et al. Deletion of G protein-coupled receptor 48 leads to ocular anterior segment dysgenesis (ASD) through down-regulation of Pitx2 PNAS, April 22, 2008; 105(16): 6081 - 6086. [Abstract] [Full Text] [PDF]

				H. P. Shih, M. K. Gross, and C. Kioussi Cranial muscle defects of Pitx2 mutants result from specification defects in the first branchial arch PNAS, April 3, 2007; 104(14): 5907 - 5912. [Abstract] [Full Text] [PDF]

				F. Dong, X. Sun, W. Liu, D. Ai, E. Klysik, M.-F. Lu, J. Hadley, L. Antoni, L. Chen, A. Baldini, et al. Pitx2 promotes development of splanchnic mesoderm-derived branchiomeric muscle Development, December 15, 2006; 133(24): 4891 - 4899. [Abstract] [Full Text] [PDF]