Msx1 and Dlx5 act independently in development of craniofacial skeleton, but converge on the regulation of Bmp signaling in palate formation

Levi, Giovanni; Mantero, Stefano; Barbieri, Ottavia; Cantatore, Daniela; Paleari, Laura; Beverdam, Annemiek; Genova, Francesca; Robert, Benoît; Merlo, Giorgio R.

doi:10.1016/j.mod.2005.10.007

Cited by 61 publications

(69 citation statements)

References 60 publications

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“…8E,G). Levi et al (Levi et al, 2006) reported wholemount in situ hybridization results for Bmp4 mRNA expression in the E13.5 palate and also clearly showed a strong Bmp4 expression domain in the posterior palate (Levi et al, 2006). We carried out section in situ hybridization of the whole series of frontal sections of E13.5 mouse palate and confirmed the separate Bmp4 mRNA expression domains in the anterior and posterior regions of the palatal shelves (Fig.…”

Section: Research Articlesupporting

confidence: 64%

“…8I,K,M). Moreover, Levi et al (Levi et al, 2006) showed that Bmp4 mRNA expression in the anterior palate, but not in the posterior palate, was reduced in the Msx1 −/− embryos in comparison with wild-type control embryos (Levi et al, 2006). We found that the posterior domain of Bmp4 mRNA expression was significantly downregulated in the Pax9 del/del mutant embryos, indicating that Pax9 regulates Bmp4 expression in the posterior palate independently of Msx1.…”

Section: Research Articlementioning

confidence: 62%

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

et al. 2013

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Cleft palate is one of the most common birth defects in humans. Whereas gene knockout studies in mice have shown that both the Osr2 and Pax9 transcription factors are essential regulators of palatogenesis, little is known about the molecular mechanisms involving these transcription factors in palate development. We report here that Pax9 plays a crucial role in patterning the anterior-posterior axis and outgrowth of the developing palatal shelves. We found that tissue-specific deletion of Pax9 in the palatal mesenchyme affected Shh expression in palatal epithelial cells, indicating that Pax9 plays a crucial role in the mesenchyme-epithelium interactions during palate development. We found that expression of the Bmp4, Fgf10, Msx1 and Osr2 genes is significantly downregulated in the developing palatal mesenchyme in Pax9 mutant embryos. Remarkably, restoration of Osr2 expression in the early palatal mesenchyme through a Pax9Osr2KI allele rescued posterior palate morphogenesis in the absence of Pax9 protein function. Our data indicate that Pax9 regulates a molecular network involving the Bmp4, Fgf10, Shh and Osr2 pathways to control palatal shelf patterning and morphogenesis.

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Section: Research Articlesupporting

confidence: 64%

Section: Research Articlementioning

confidence: 62%

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

et al. 2013

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“…Inactivation of Dlx5 leads to an expansion of the oral region of the palatal shelf Previous studies examining Dlx5 -/-mice were based on skeletal staining, which revealed incomplete palatal bone fusion (Depew et al, 1999;Levi et al, 2006). In order to characterize the palatal phenotype thoroughly, we performed scanning electron microscopy (SEM) on Dlx5 -/-mice.…”

Section: Oronasal Patterning Of Mouse Palatal Mesenchymementioning

confidence: 99%

Indirect modulation of Shh signaling by Dlx5 affects the oral-nasal patterning of palate and rescues cleft palate in Msx1-null mice

et al. 2009

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Cleft palate represents one of the most common congenital birth defects in human. During embryonic development, palatal shelves display oronasal (O-N) and anteroposterior polarity before the onset of fusion, but how the O-N pattern is established and how it relates to the expansion and fusion of the palatal shelves are unknown. Here we address these questions and show that O-N patterning is associated with the expansion and fusion of the palatal shelves and that Dlx5 is required for the O-N patterning of palatal mesenchyme. Loss of Dlx5 results in downregulation of Fgf7 and expanded Shh expression from the oral to the nasal side of the palatal shelf. This expanded Shh signaling is sufficient to restore palatal expansion and fusion in mice with compromised palatal mesenchymal cell proliferation, such as Msx1-null mutants. Exogenous Fgf7 inhibits Shh signaling and reverses the cranial neural crest (CNC) cell proliferation rescue in the Msx1/Dlx5 double knockout palatal mesenchyme. Thus, Dlx5-regulated Fgf7 signaling inhibits the expression of Shh, which in turn controls the fate of CNC cells through tissue-tissue interaction and plays a crucial role during palatogenesis. Our study shows that modulation of Shh signaling may be useful as a potential therapeutic approach for rescuing cleft palate.

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“…For each probe, two normal and two mutant specimens were examined. Section and whole-mount hybridization was done according to published procedures (Levi et al, 2006).…”

Section: Immunohistochemistry and In Situ Hybridizationmentioning

confidence: 99%

Regulation ofDlx5andDlx6gene expression by p63 is involved in EEC and SHFM congenital limb defects

et al. 2008

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The congenital malformation Split Hand-Foot Malformation (SHFM, or ectrodactyly) is characterized by a medial cleft of hands and feet, and missing central fingers. Five genetically distinct forms are known in humans; the most common (type-I) is linked to deletions of DSS1 and the distalless-related homeogenes DLX5 and DLX6. As Dlx5;Dlx6 double-knockout mice show a SHFM-like phenotype, the human orthologs are believed to be the disease genes. SHFM-IV and Ectrodactyly-Ectodermal dysplasia-Cleft lip (EEC) are caused by mutations in p63, an ectoderm-specific p53-related transcription factor. The similarity in the limb phenotype of different forms of SHFM may underlie the existence of a regulatory cascade involving the disease genes. Here, we show that p63 and Dlx proteins colocalize in the nuclei of the apical ectodermal ridge (AER). In homozygous p63-(null) and p63 EEC (R279H) mutant limbs, the AER fails to stratify and the expression of four Dlx genes is strongly reduced; interestingly, the p63 +/EEC and p63hindlimbs, which develop normally and have a normally stratified AER, show reduced Dlx gene expression. The p63 +/EEC mutation combined with an incomplete loss of Dlx5 and Dlx6 alleles leads to severe limb phenotypes, which are not observed in mice with either mutation alone. In vitro, ⌬Np63␣ induces transcription from the Dlx5 and Dlx6 promoters, an activity abolished by EEC and SHFM-IV mutations, but not by Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) mutations. ChIP analysis shows that p63 is directly associated with the Dlx5 and Dlx6 promoters. Thus, our data strongly implicate p63 and the Dlx5-Dlx6 locus in a pathway relevant in the aetio-pathogenesis of SHFM.

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Msx1 and Dlx5 act independently in development of craniofacial skeleton, but converge on the regulation of Bmp signaling in palate formation

Cited by 61 publications

References 60 publications

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

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

Indirect modulation of Shh signaling by Dlx5 affects the oral-nasal patterning of palate and rescues cleft palate in Msx1-null mice

Regulation ofDlx5andDlx6gene expression by p63 is involved in EEC and SHFM congenital limb defects

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