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Prx1 and Prx2 are upstream regulators of sonic hedgehog and control cell proliferation during mandibular arch

D ten Berge1, A Brouwer, J Korving

  • 1Hubrecht Laboratorium, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.

Development (Cambridge, England)
|September 5, 2001
PubMed

Insights

Aristaless-related homeobox genes Prx1 and Prx2 are crucial for skeletal development. Their absence causes severe jaw defects, linked to reduced sonic hedgehog (Shh) signaling, impacting mandibular arch morphogenesis.

Area of Science:

  • Developmental Biology
  • Genetics
  • Craniofacial Development

Background:

  • Aristaless-related homeobox ( Arx) genes, specifically Prx1 and Prx2, play vital roles in skeletal development.
  • Mutations in Prx1 and Prx2 lead to significant reductions or absence of skeletal elements in various body parts, including the skull, face, limbs, and vertebral column.
  • A notable phenotype in Prx1(-/-)Prx2(-/-) mice is the malformation of the lower jaw, characterized by midline structure loss and a single, medially positioned incisor.

Purpose of the Study:

  • To investigate the developmental mechanisms underlying the lower jaw abnormalities observed in Prx1(-/-)Prx2(-/-) mutant mice.
  • To elucidate the molecular basis for the observed craniofacial defects, particularly in the mandibular arch.
  • To understand the role of Prx genes in the regulation of signaling pathways involved in jaw development.

Main Methods:

  • Analysis of Prx1(-/-)Prx2(-/-) mutant mouse embryos to examine mandibular arch development.
  • Assessment of cell proliferation in the mandibular arch mesenchyme.
  • In situ hybridization to analyze gene expression patterns, focusing on sonic hedgehog (Shh).
  • Pharmacological inhibition of the hedgehog pathway in wild-type embryos using jervine to compare phenotypic outcomes.

Main Results:

  • Mutant embryos exhibited a localized decrease in mandibular arch mesenchyme proliferation in the medial region.
  • A significant reduction in sonic hedgehog (Shh) expression was observed in the oral epithelium adjacent to the affected mesenchyme.
  • Pharmacological inhibition of the hedgehog pathway in wild-type embryos partially mimicked the jaw defects and caused loss of mandibular incisors.

Conclusions:

  • Prx1 and Prx2 genes are essential for normal mandibular arch development.
  • Loss of Prx1 and Prx2 function leads to reduced mesenchyme proliferation and downregulates Shh expression.
  • A model is proposed where reduced Shh signaling, secondary to Prx gene loss, underlies the abnormal mandibular arch morphogenesis and associated craniofacial defects.

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