Pax3 induces cell aggregation

In a theoretical model of morphogenesis, Atchley and Hall (Atchley and Hall, 1991) proposed cell condensation, the aggregation of like cells, as the basic unit from which morphology is constructed during development. Indeed, cell condensation is an early developmental process in essentially every organ during vertebrate embryogenesis (Thesleff et al., 1995). Likewise, transformations between the two major phenotypic cell types, epithelial and mesenchymal, play an important role in the genesis and patterning of numerous tissues and organs during development (Hay, 1995). Mesenchymal condensation and mesenchymal-to-epithelial transformations play pivotal roles in the formation and patterning of, for example, somitic (Christ and Ordahl, 1995) and kidney (Davies, 1996) structures. Aborted organogenesis at the point of mesenchymal condensation or cell aggregation is a feature common to mice with mutations in distinct Pax genes (Dahl et al., 1997). The Pax-family genes encode a class of transcription factors that are essential for normal embryonic development. Originally identified as regulators of pattern formation during Drosophila embryogenesis, nine different Pax genes have been identified in mammals, Pax1 to Pax9 (Walther et al., 1991), all of which encode proteins containing a DNA-binding motif termed the paired box (Noll, 1993). Analyses of animals harboring naturally occurring or targeted mutations of different Pax genes revealed their fundamental requirement for orchestrating proper morphological development of various tissues and organs (Dahl et al., 1997). Some of the many examples include Pax3 mutant mice, where maintenance of epithelial aggregation in somitic cells of the dermomyotome is lost (Daston et al., 1996), and Pax2 mutant mice, in which aborted kidney development occurs due to the failure of the metanephric mesenchyme to condense and undergo epithelial transformation (Torres et al., 1995). For these mutant animals, a role for Pax proteins in regulating cell aggregation/mesenchymal condensation and/or mesenchymalto-epithelial transformation has been implied. During mouse embryogenesis, Pax3 is expressed in several developing tissues including the brain, dorsally throughout the neural tube, in neural crest cells, the dermomyotome and in migratory somitic muscle precursors (Goulding et al., 1991). Mutations to Pax3 in mice results in the splotch (sp) phenotype (Epstein et al., 1991). Homozygous mutant sp embryos exhibit a number of developmental defects including impaired neural tube closure, absence of limb muscles, persistent truncus arteriosus and defects to many neural crest-derived structures (Auerbach, 1954; Franz, 1989; Franz et al., 1993). In humans, heterozygous mutations to Pax3 cause Waardenburg syndrome, which is characterized by pigmentation, and hearing and facioskeletal anomalies (Baldwin et al., 1992; Tassabehji et al., 1992). Recent studies have begun to provide insights into the cellular and molecular processes that Pax genes may regulate during embryogenesis. During muscle development, for example, Pax3 appears to regulate the expression of myogenic determination factors (Maroto et al., 1997; Tajbakhsh et al., 1997) as well as migration of muscle precursors via regulation of c-met expression (Daston et al., 1996; Epstein et al., 1996; Yang et al., 1996). However, the cellular and molecular mechanisms by which Pax3 specifically regulates morphogenesis remains elusive. 517