Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities

Abstract

Pax genes have been shown to play important roles in mammalian development and organogenesis. Pax9, a member of this transcription factor family, is expressed in somites, pharyngeal pouches, mesenchyme involved in craniofacial, tooth, and limb development, as well as other sites during mouse embryogenesis. To analyze its function in vivo, we generated Pax9 deficient mice and show that Pax9 is essential for the development of a variety of organs and skeletal elements. Homozygous Pax9-mutant mice die shortly after birth, most likely as a consequence of a cleft secondary palate. They lack a thymus, parathyroid glands, and ultimobranchial bodies, organs which are derived from the pharyngeal pouches. In all limbs, a supernumerary preaxial digit is formed, but the flexor of the hindlimb toes is missing. Furthermore, craniofacial and visceral skeletogenesis is disturbed, and all teeth are absent. In Pax9-deficient embryos tooth development is arrested at the bud stage. At this stage, Pax9 is required for the mesenchymal expression of Bmp4, Msx1, and Lef1, suggesting a role for Pax9 in the establishment of the inductive capacity of the tooth mesenchyme. In summary, our analysis shows that Pax9 is a key regulator during the development of a wide range of organ primordia.

Msx1 and Msx2 in limb mesenchyme modulate digit number and identity

“…Furthermore, in this organ, defects induced by Msx1 Pax9 double heterozygous null mutations could be partially rescued by a Bmp4 transgene. Pax9, Msx1, and Msx2 are also coexpressed in the presumptive territory of the thumb at 11.5 dpc (Neubuser et al, 1995), and a Pax9 null mutation, similarly to Msx gene conditional mutation, leads to preaxial digit duplication (Peters et al, 1998). Our results confirm that, in the limb, Msx activity controls Pax9 expression, as we previously showed (Lallemand et al, 2009), and second, suggest that in this field too, Msx and Pax9 proteins might interact to control Bmp4 expression.…”

Distribution of the titf2/foxe1 gene product is consistent with an important role in the development of foregut endoderm, palate, and hair

“…On the contrary, many other genes expressed in the pharynx, such as Pax9 (Peters et al, 1998), Pax1 (Wallin et al, 1996), Hoxa-3 (Manley and Capecchi, 1995), Fgf3 (Wendling et al, 2000), Fgf8 (Crossley and Martin, 1995), Hex (Martinez Barbera et al, 2000), are expressed in the endodermal layer of some or all pharyngeal pouches in addition to other tissues. Hence, TTF-2 is a useful marker for the epithelial component of all the structures originating from arches and wall of pharynx: thyroid, tongue, epiglottis, palate, and oesophagus; indeed it is absent in the laryngotracheal groove and its derivatives, trachea, and lungs.…”

Expression survey of genes critical for tooth development in the human embryonic tooth germ

“…Knockout of Msx1, Pax9, or Pitx2 in mice causes failed tooth development (Satakata and Maas, 1994;Peters et al, 1998;Lin et al, 1999;Lu et al, 1999). In humans, mutations in each of these genes are also associated with tooth phenotypes, including tooth agenesis and oligodontia (Semina et al, 1996;Vastardis et al, 1996;Van den Boogaard et al, 2000;Lidral and Reising, 2002;Stockton et al, 2002).…”

“…For example, Bmp4 induces Msx1 but represses Pax9 expression, whereas Fgf8 induces Pax9 expression during the determination of tooth forming sites (Vainio et al, 1993;Chen et al, 1996;Neubuser et al, 1997) On the other hand, Msx1 and Pax9 regulate the expression of Bmp4 (Chen et al, 1996;Peters et al, 1998). Fgf8 positively but Bmp4 negatively regulates Pitx2 expression (St. Amand et al, 2000), while Pitx2 in turn positively regulates Fgf8 expression (Lin et al, 1999;Lu et al, 1999).…”

“…The tooth phenotype seen in mouse mutants is sometimes found in humans carrying mutations in the counterpart genes. For example, mutations in either Msx1 or Pax9 in mice lead to the arrest of tooth development at the bud stage (Satokata and Maas, 1994;Chen et al, 1996;Peters et al, 1998). In humans, mutations in the MSX1 gene or PAX9 gene also cause tooth agenesis or oligodontia, respectively (Vastardis et al, 1996;Van den Boogaard et al, 2000;Lidral and Reising, 2002;Stockton et al, 2002).…”