Pitx2c overexpression promotes cell proliferation and arrests differentiation in myoblasts

Martínez-Fernández, Sergio; Hernández-Torres, Francisco; Franco, Diego; Lyons, Gary E.; Navarro, Francisco; Aránega, Amelia

doi:10.1002/dvdy.20924

Cited by 44 publications

(34 citation statements)

References 37 publications

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“…Combined with previous findings, in other cellular contexts where CyclinD1 is a direct target of Pitx2 (42,43,46,47), our results suggest that the Pitx2-CyclinD pathway might be a prototypic module used to regulate cell-type-specific proliferation during embryogenesis. However, the fact that CyclinD1 is not sufficient to completely rescue the degeneration of the right gonad indicates the presence of other factors/mechanisms acting in parallel and/or in conjunction with CyclinD1, and downstream of Pitx2, during gonad outgrowth and differentiation.…”

Section: Subcellular Asymmetries Of the Left Versus Right Female Chicsupporting

confidence: 86%

Pitx2 regulates gonad morphogenesis

Rodríguez-León

Esteban

Martí

et al. 2008

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

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Organ shape and size, and, ultimately, organ function, relate in part to the cell and tissue spatial arrangement that takes place during embryonic development. Despite great advances in the genetic regulatory networks responsible for tissue and organ development, it is not yet clearly understood how specific gene functions are linked to the specific morphogenetic processes underlying the internal organ asymmetries found in vertebrate animals. During female chick embryogenesis, and in contrast to males where both testes develop symmetrically, asymmetrical gonad morphogenesis results in only one functional ovary. The disposition of paired organs along the left-right body axis has been shown to be regulated by the activity of the homeobox containing gene pitx2. We have found that pitx2 regulates cell adhesion, affinity, and cell recognition events in the developing gonad primordium epithelia. This in turn not only allows for proper somatic development of the gonad cortex but also permits the proliferation and differentiation of primordial germ cells. We illustrate how Pitx2 activity directs asymmetrical gonad morphogenesis by controlling mitotic spindle orientation of the developing gonad cortex and how, by modulating cyclinD1 expression during asymmetric ovarian development, Pitx2 appears to control gonad organ size. All together our observations indicate that the effects elicited by Pitx2 during the development of the female chick ovary are critical for cell topology, growth, fate, and ultimately organ morphogenesis and function.cyclin D1 ͉ left-right asymmetry ͉ chick ovary development ͉ mitotic orientation ͉ primordial germ cell D espite the initial bilateral symmetry of the vertebrate body plan, internal organs, such as the heart, stomach, and intestines, all have a characteristic asymmetric structure and are asymmetrically positioned in the body cavity. The acquisition of proper left-right asymmetries is achieved in a highly conserved manner during embryo development. Since the seminal work more than a decade ago that identified a functional link between asymmetrical gene expression and organ asymmetry (1), our understanding of the molecular and cellular events involved in the establishment of left-right asymmetry in vertebrates has increased enormously. This is indeed the case in the initial establishment of left-right asymmetrical differences that occur during gastrulation as well as during the immediately subsequent stages of embryo development when the local asymmetrical cues in and around the node are deployed to broader domains of gene expression in the lateral plate mesoderm. Once side-specific gene expression domains are established and stabilized in the lateral plate mesoderm, left-right information is transferred to the organ primordial, where left and right side-specific morphogenetic programs are executed (reviewed in refs. 2-6).The identification of several genes that display side-specific patterns of expression within the developing organs has provided an entry point for understanding the molecu...

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Section: Subcellular Asymmetries Of the Left Versus Right Female Chicsupporting

confidence: 86%

Pitx2 regulates gonad morphogenesis

Rodríguez-León

Esteban

Martí

et al. 2008

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

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“…23), and Pitx2 (ref. 24). We note that this dictionary of candidate regulatory motifs contained matches to the MRF, MEF2 and Tead motifs, all of which were again observed to be statistically significantly enriched in various gene sets (see Supplementary Table 3 online).…”

Section: Lever Screen Of 174 Candidate Regulatory Motifs Across 101 Mmentioning

confidence: 71%

Systematic identification of mammalian regulatory motifs' target genes and functions

et al. 2008

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We have developed an algorithm ("Lever") that systematically maps metazoan DNA regulatory motifs or motif combinations to the sets of genes that they likely regulate. Lever accomplishes this by assessing whether the motifs are enriched within cis regulatory modules (CRMs), predicted by our "PhylCRM" algorithm, in the noncoding sequences surrounding genes in a collection of gene sets. When these gene sets correspond to Gene Ontology (GO) categories, the results of Lever analysis allow the unbiased assignment of functional annotations to the regulatory motifs and also to the candidate CRMs that comprise the genomic motif occurrences. We demonstrate these methods using human myogenic differentiation as a model system, for which we statistically assessed greater than 25,000 pairings of gene sets and motifs / motif combinations. These results allowed us to assign functional annotations to candidate regulatory motifs predicted previously, and to identify gene sets that are likely to be co-regulated via shared regulatory motifs. Lever allows moving beyond the identification of putative regulatory motifs in mammalian genomes, towards understanding their biological roles. This approach is general and can be applied readily to any cell type, gene expression pattern, or organism of interest.

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“…These genes, Pitx2, Alx4, MyoR (musculin) and Tbx1, label and pattern the tissue prior to the onset of differentiation; they also distinguish head-derived muscle satellite cells (adult muscle stem cells) from satellite cells in the trunk (Harel et al, 2009;Sambasivan et al, 2009). Pitx2, MyoR and Tbx1 have been shown to keep cells in an undifferentiated, proliferative precursor state, but contribute to the onset of myogenesis in a similar fashion as Pax3 in the somite (Kioussi et al, 2002;Lu et al, 1999;Martinez-Fernandez et al, 2006;Sambasivan et al, 2009;Xu et al, 2004). Mutations of the genes cause specific defects in the head musculature and outflow tract of the heart Dong et al, 2006;Gage et al, 1999;Kelly et al, 2004;Kitamura et al, 1999;Liu et al, 2002;Lu et al, 2002;Nowotschin et al, 2006;Shih et al, 2007;Vitelli et al, 2002a;Vitelli et al, 2002b;Xu et al, 2004) (for reviews, see Baldini, 2002;Bothe et al, 2007;Noden and Francis-West, 2006;Rochais et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Dynamic control of head mesoderm patterning

et al. 2011

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SUMMARYThe embryonic head mesoderm gives rise to cranial muscle and contributes to the skull and heart. Prior to differentiation, the tissue is regionalised by the means of molecular markers. We show that this pattern is established in three discrete phases, all depending on extrinsic cues. Assaying for direct and first-wave indirect responses, we found that the process is controlled by dynamic combinatorial as well as antagonistic action of retinoic acid (RA), Bmp and Fgf signalling. In phase 1, the initial anteroposterior (a-p) subdivision of the head mesoderm is laid down in response to falling RA levels and activation of Fgf signalling. In phase 2, Bmp and Fgf signalling reinforce the a-p boundary and refine anterior marker gene expression. In phase 3, spreading Fgf signalling drives the a-p expansion of MyoR and Tbx1 expression along the pharynx, with RA limiting the expansion of MyoR. This establishes the mature head mesoderm pattern with markers distinguishing between the prospective extra-ocular and jaw skeletal muscles, the branchiomeric muscles and the cells for the outflow tract of the heart.

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Pitx2c overexpression promotes cell proliferation and arrests differentiation in myoblasts

Cited by 44 publications

References 37 publications

Pitx2 regulates gonad morphogenesis

Pitx2 regulates gonad morphogenesis

Systematic identification of mammalian regulatory motifs' target genes and functions

Dynamic control of head mesoderm patterning

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