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Persistent expression of Pax3 in the neural crest causes cleft palate and defective osteogenesis in mice
Meilin Wu, … , Joshua B. Plotkin, Jonathan A. Epstein
Meilin Wu, … , Joshua B. Plotkin, Jonathan A. Epstein
Published May 15, 2008
Citation Information: J Clin Invest. 2008;118(6):2076-2087. https://doi.org/10.1172/JCI33715.
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Research Article Development Article has an altmetric score of 3

Persistent expression of Pax3 in the neural crest causes cleft palate and defective osteogenesis in mice

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Abstract

Transcription factors regulate tissue patterning and cell fate determination during development; however, expression of early regulators frequently abates upon differentiation, suggesting that they may also play a role in maintaining an undifferentiated phenotype. The transcription factor paired box 3 (Pax3) is expressed by multipotent neural crest precursors and is implicated in neural crest disorders in humans such as Waardenburg syndrome. Pax3 is required for development of multiple neural crest lineages and for activation of lineage-specific programs, yet expression is generally extinguished once neural crest cells migrate from the dorsal neural tube and differentiate. Using a murine Cre-inducible system, we asked whether persistent Pax3 expression in neural crest derivatives would affect development or patterning. We found that persistent expression of Pax3 in cranial neural crest cells resulted in cleft palate, ocular defects, malformation of the sphenoid bone, and perinatal lethality. Furthermore, we demonstrated that Pax3 directly regulates expression of Sostdc1, a soluble inhibitor of bone morphogenetic protein (BMP) signaling. Persistent Pax3 expression renders the cranial crest resistant to BMP-induced osteogenesis. Thus, one mechanism by which Pax3 maintains the undifferentiated state of neural crest mesenchyme may be to block responsiveness to differentiation signals from the environment. These studies provide in vivo evidence for the importance of Pax3 downregulation during differentiation of multipotent neural crest precursors and cranial development.

Authors

Meilin Wu, Jun Li, Kurt A. Engleka, Bo Zhou, Min Min Lu, Joshua B. Plotkin, Jonathan A. Epstein

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Figure 1

Pax3 knockin at Rosa26 locus.

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Pax3 knockin at Rosa26 locus.
   
(A) The murine Pax3 cDNA was inserted ...
(A) The murine Pax3 cDNA was inserted downstream of a PGK-neo cassette with a transcriptional stop signal flanked by 2 loxP sites in the pBigT plasmid containing the Rosa26 genomic sequence. Homologous recombination between the Rosa26Pax3 construct and the appropriate genomic locus resulted in a targeted allele where Pax3 is expressed only after Cre-mediated recombination. A probe for Southern blot confirmation of homologous recombination is indicated. (B) Southern blot analysis of WT and R26Pax3/+EcoRV-digested genomic DNA from wild-type and targeted ES cells showing wild-type and knockin (KI) bands. (C) Western blot of lysates from uninfected (lane 1) mouse embryonic stem cells targeted with R26Pax3/+ or infected with Cre-adenovirus (lane 2) with Pax3 antibody. Pax3 protein from transfected 293T cells was used as a positive control (lane 3). (D) Cre-adenovirus–infected R26Pax3/+ ES cells immunostained with Pax3 antibody. Original magnification, ×100. (E) Immunohistochemistry to detect Pax3 protein in the smooth muscle layer of the aortic arch (arrows) of E16.5 embryos. Pax3 protein is detected in R26Pax3/Pax3 embryos only when Pax3Cre (right panel) is present. Endothelial and luminal staining is artifactual. Pax3 staining is nuclear. Original magnification, ×25. (F) Western blot to detect Pax3 protein in E11.5 whole-embryo lysates. Actin is shown as control, and relative pixel density is indicated below each lane.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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