Pax9 regulates a molecular network involving Bmp4, Fgf10, Shh signaling and the Osr2 transcription factor to control palate morphogenesis

Zhou, Jing; Gao, Yang; Lan, Yu; Jia, Shihai; Jiang, Rulang

doi:10.1242/dev.099028

Cited by 89 publications

(165 citation statements)

References 42 publications

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“…However, the changes in Osr2 and Pax9 expression were more pronounced in the middle palate than in the posterior palate, and thus did not correlate with the relative severities of the elevation defect. Furthermore, while the morphologies of the anterior and middle palate are very similar between Pax9 −/− mutants and Wnt1-Cre;Ldb1 fl/- mutants (such as the absence of the indentation medial to the upper molar) [26,27], the phenotypes differ in the posterior palate. In Pax9 −/− mutants, the posterior palate became horizontal by E15.5, indicating that there is a delay but not a failure in palatal elevation [27].…”

Section: Discussionmentioning

confidence: 99%

Neural crest-specific deletion of Ldb1 leads to cleft secondary palate with impaired palatal shelf elevation

et al. 2014

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BackgroundLIM domain binding protein 1 (LDB1) is a transcriptional co-factor, which interacts with multiple transcription factors and other proteins containing LIM domains. Complete inactivation of Ldb1 in mice resulted in early embryonic lethality with severe patterning defects during gastrulation. Tissue-specific deletions using a conditional knockout allele revealed additional roles of Ldb1 in the development of the central nervous system, hematopoietic system, and limbs. The goal of the current study was to determine the importance of Ldb1 function during craniofacial development in mouse embryos.ResultsWe generated tissue-specific Ldb1 mutants using Wnt1-Cre, which causes deletion of a floxed allele in the neural crest; neural crest-derived cells contribute to most of the mesenchyme of the developing face. All examined Wnt1-Cre;Ldb1 fl/- mutants suffered from cleft secondary palate. Therefore, we performed a series of experiments to investigate how Ldb1 regulated palate development. First, we examined the expression of Ldb1 during normal development, and found that Ldb1 was expressed broadly in the palatal mesenchyme during early stages of palate development. Second, we compared the morphology of the developing palate in control and Ldb1 mutant embryos using sections. We found that the mutant palatal shelves had abnormally blunt appearance, and failed to elevate above the tongue at the posterior domain. An in vitro head culture experiment indicated that the elevation defect was not due to interference by the tongue. Finally, in the Ldb1 mutant palatal shelves, cell proliferation was abnormal in the anterior, and the expression of Wnt5a, Pax9 and Osr2, which regulate palatal shelf elevation, was also altered.ConclusionsThe function of Ldb1 in the neural crest-derived palatal mesenchyme is essential for normal morphogenesis of the secondary palate.

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Section: Discussionmentioning

confidence: 99%

Neural crest-specific deletion of Ldb1 leads to cleft secondary palate with impaired palatal shelf elevation

et al. 2014

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“…Palatal cell proliferation was analyzed as described previously (Lan et al, 2004;Xu et al, 2015;Zhou et al, 2013). The numbers of BrdU-labeled nuclei and total nuclei were recorded for five independent control and mutant littermate pairs.…”

Section: Histology Western Blotting Cell Proliferation Analysis Andmentioning

confidence: 99%

“…Skeletal preparations of E18 and P0 pups were performed as described previously (Liu et al, 2013;Zhou et al, 2013).…”

Section: Histology Western Blotting Cell Proliferation Analysis Andmentioning

confidence: 99%

Golgb1 regulates protein glycosylation and is crucial for mammalian palate development

et al. 2016

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Cleft palate is a common major birth defect for which currently known causes account for less than 30% of pathology in humans. In this study, we carried out mutagenesis screening in mice to identify new regulators of palatogenesis. Through genetic linkage mapping and whole exome sequencing, we identified a loss-of-function mutation in the Golgb1 gene that co-segregated with cleft palate in a new mutant mouse line. Golgb1 encodes a ubiquitously expressed large coiled-coil protein, known as giantin, that is localized at the Golgi membrane. Using CRISPR/Cas9-mediated genome editing, we generated and analyzed developmental defects in mice carrying additional Golgb1 loss-of-function mutations, which validated a critical requirement for Golgb1 in palate development. Through maxillary explant culture assays, we demonstrate that the Golgb1 mutant embryos have intrinsic defects in palatal shelf elevation. Just prior to the developmental stage of palatal shelf elevation in the wildtype littermates, Golgb1 mutant embryos exhibit increased cell density, reduced hyaluronan accumulation, and impaired protein glycosylation in the palatal mesenchyme. Together, these results demonstrate that, although it is a ubiquitously expressed Golgi-associated protein, Golgb1 has specific functions in protein glycosylation and tissue morphogenesis.

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“…[34] Osr2 is involved in regulating palatal shelf elevation and functions as a downstream target of Pax9 during palatogenesis. [35,36] The downregulation of Runx2 (-2.66 fold; p<0.05) and Osr2 (-2.08 fold; p<0.01) in CL/Fr tissues may indicate a secondary effect resulting in cleft palate. Further investigation is necessary to confirm the expression values of these genes and to identify their role in craniofacial morphogenesis.…”

Section: Tablementioning

confidence: 99%

Reduction in Wnt9b and associated gene expression in the embryonic midface of CL/Fr mice with heritable cleft lip and palate

Takagi¹,

Hong²,

Hynd³

et al. 2016

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Objectives: The CL/Fr mouse displays cleft lip and palate (CLP) at a rate of 35%. The clf1 mutation is associated with CLP in related "A" strain mice and affects the gene Wnt9b. The purpose of this study was to determine tissue specific expression of Wnt9b during facial prominence morphogenesis in CL/Fr mice and provide new details concerning gene variants associated with CLP. Methods:Facial prominences from CLP(-) and CLP(+) CL/Fr and 3H1 wild-type (WT) mice at embryonic day 11.5 (E11.5) were collected for expression assays (DNA microarray analysis, qRT-PCR, immunostaining, and in situ hybridization). A modified Chi square test was used to analyze microarray data while a student t-test was used to statistically compare qRT-PCR values (p<0.05).Results: There was a partial and variable loss of Wnt9b in facial prominences of E11.5 CLP susceptible CL/Fr mice, with a greater loss associated with CLP(+). Two genes in the clf2 locus, Adcy2 and Ube2q11 also showed decreased expression. Two regulators of palatogenesis, Runx2 and Osr2 were significantly downregulated, while an inhibitor of cell proliferation, somatostatin (Sst), was elevated in CLP(+) relative to CLP(-) mice. Conclusion:Results indicate a role for Wnt9b in the pathogenesis of CLP and supports previous reports concerning its involvement with CLP in "A" strain mice. Misexpression of Sst suggests that it may be a downstream target of Wnt9b causing reduced overall growth possibly hindering fusion of facial prominences and contributing to the development of CLP.

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Pax9 regulates a molecular network involving Bmp4, Fgf10, Shh signaling and the Osr2 transcription factor to control palate morphogenesis

Cited by 89 publications

References 42 publications

Neural crest-specific deletion of Ldb1 leads to cleft secondary palate with impaired palatal shelf elevation

Neural crest-specific deletion of Ldb1 leads to cleft secondary palate with impaired palatal shelf elevation

Golgb1 regulates protein glycosylation and is crucial for mammalian palate development

Reduction in Wnt9b and associated gene expression in the embryonic midface of CL/Fr mice with heritable cleft lip and palate

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