Extraocular Muscle Morphogenesis and Gene Expression Are Regulated by<i>Pitx2</i>Gene Dose

Diehl, Adam; Zareparsi, Sepideh; Qian, Min; Khanna, Ritu; Angeles, Rowena; Gage, Philip J.

doi:10.1167/iovs.05-1424

Cited by 89 publications

(80 citation statements)

References 52 publications

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“…Muscle anlagen that are entirely associated with the missing structures are absent (body wall muscles, mandibular adductors, intermandibular). Some extraocular muscle precursors fail to condense in Pitx2 mutants and their expression of myogenic markers is aborted (17) (30). Some extraocular muscles and the mastication muscles that connect maxilla and mandible to other regions of the skull are derived from the first BA, which is vestigial in Pitx2 mutants by E13.5.…”

Section: Discussionmentioning

confidence: 99%

Cranial muscle defects of Pitx2 mutants result from specification defects in the first branchial arch

Shih

Groß

Kioussi³

2007

Proc. Natl. Acad. Sci. U.S.A.

116

143

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Pitx2 expression is observed during all states of the myogenic progression in embryonic muscle anlagen and persists in adult muscle. Pitx2 mutant mice form all but a few muscle anlagen. Loss or degeneration in muscle anlagen could generally be attributed to the loss of a muscle attachment site induced by some other aspect of the Pitx2 phenotype. Muscles derived from the first branchial arch were absent, whereas muscles derived from the second branchial arch were merely distorted in Pitx2 mutants at midgestation. Pitx2 was expressed well before, and was required for, initiation of the myogenic progression in the first, but not second, branchial arch mesoderm. Pitx2 was also required for expression of premyoblast specification markers Tbx1, Tcf21, and Msc in the first, but not second, branchial arch. First, but not second, arch mesoderm of Pitx2 mutants failed to enlarge after embryonic day 9.5, well before the onset of the myogenic progression. Thus, Pitx2 contributes to specification of first, but not second, arch mesoderm. The jaw of Pitx2 mutants was vestigial by midgestation, but significant size reductions were observed as early as embryonic day 10.5. The diminutive first branchial arch of mutants could not be explained by loss of mesoderm alone, suggesting that Pitx2 contributes to the earliest specification of jaw itself.homeobox gene ͉ muscle development

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Section: Discussionmentioning

confidence: 99%

Cranial muscle defects of Pitx2 mutants result from specification defects in the first branchial arch

Shih

Groß

Kioussi³

2007

Proc. Natl. Acad. Sci. U.S.A.

116

143

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“…The Pitx2 gene has previously been shown to be expressed during embryonic myogenesis (Diehl et al, 2006;Dong et al, 2006;L'Honoré et al, 2007;Shih et al, 2007b) of different skeletal muscle types, including extraocular, branchiomeric, trunk and limb muscles. Whereas Pitx2 was suggested to regulate MRF transcription in extraocular and branchiomeric muscles (Diehl et al, 2006;Dong et al, 2006), it was also implicated in proliferation and survival of muscle progenitor cells in branchiomeric muscles (Dong et al, 2006;Shih et al, 2007a).…”

Section: Introductionmentioning

confidence: 99%

“…Whereas Pitx2 was suggested to regulate MRF transcription in extraocular and branchiomeric muscles (Diehl et al, 2006;Dong et al, 2006), it was also implicated in proliferation and survival of muscle progenitor cells in branchiomeric muscles (Dong et al, 2006;Shih et al, 2007a). During body muscle development, Pitx2 is expressed in muscle progenitor cells and early differentiating cells and its expression decreases at terminal differentiation Shih et al, 2007b).…”

Section: Introductionmentioning

confidence: 99%

Pitx2 defines alternate pathways acting through MyoD during limb and somitic myogenesis

et al. 2010

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SUMMARYThe MyoD gene is part of the core regulatory network that governs skeletal myogenesis and acts as an essential determinant of the myogenic cell fate. Although generic regulatory networks converging on this gene have been described, the specific mechanisms leading to MyoD expression in muscles of different ontology remain misunderstood. We now show that the homeobox gene Pitx2 is required for initial activation of the MyoD gene in limb muscle precursors through direct binding of Pitx2 to the MyoD core enhancer. Whereas Myf5 and Mrf4 are dispensable for limb muscle progenitor fate, inactivation of Myf5 and Mrf4 in Pitx2 mutants results in a drastic decrease of limb MyoD expression. Thus, Pitx2 and Myf5 define parallel genetic pathways for limb myogenesis. We show a similar dependence on Pitx2 and Myf5(Mrf4) in myotome, where MyoD expression is initially activated by Myf5 and Mrf4. In their absence, MyoD expression is eventually rescued by a Pax3-dependent mechanism. We now provide evidence that Pitx2 contributes to the rescue of MyoD expression and that it acts downstream of Pax3. We thus propose that myogenic differentiation of somite-derived muscle cells relies on two parallel genetic pathways, with the Pitx2 pathway being of primary importance for limb myogenesis but the Myf5 and Mrf4 pathway predominating in myotome. Musclespecific wiring of regulatory networks composed of similar transcription factors thus underlies development of distinct skeletal muscles.

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“…Whether this is an example of cell differentiation being dependent on its function, or simply a coincidence, we do not know at this point, and we could not address it more directly than we already have (Kablar, 2003), unless we were provided with another mouse mutant without extraocular musculature and examined its neural retina. For instance, Pitx2 nulls apparently specifically lack the extraocular muscles and they are viable at term (Diehl et al, 2006), therefore representing an ideal occasion for testing our hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Abnormal retinal development in the Btrc null mouse

Baguma-Nibasheka

Kablar

2009

Developmental Dynamics

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Previous microarray analysis revealed beta-transducin repeat containing (Btrc) down-regulation in the retina of mouse embryos specifically lacking cholinergic amacrine cells (CACs) as a result of the absence of skeletal musculature and fetal ocular movements. To investigate the role of Btrc in the determination of retinal cell fate, the present study examined retinal morphology in Btrc؊/؊ mouse fetuses. The Btrc؊/؊ retina showed a normal number of cell layers and number of cells per layer with normal cell proliferation and apoptosis. However, there was a complete absence of CACs and a decrease in tyrosine hydroxylaseexpressing amacrine cells. The population of other amacrine cell subtypes was normal, whereas that of the precursor cells was decreased. There was also a reduction in the number of retinal ganglion cells, whereas their progenitors were increased. These findings suggest a role for Btrc in regulating the eventual ratio of resulting differentiated retinal cell types.

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Extraocular Muscle Morphogenesis and Gene Expression Are Regulated byPitx2Gene Dose

Cited by 89 publications

References 52 publications

Cranial muscle defects of Pitx2 mutants result from specification defects in the first branchial arch

Cranial muscle defects of Pitx2 mutants result from specification defects in the first branchial arch

Pitx2 defines alternate pathways acting through MyoD during limb and somitic myogenesis

Abnormal retinal development in the Btrc null mouse

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