Pax3 overexpression induces cell aggregation and perturbs commissural axon projection during embryonic spinal cord development

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Vertebrate Pax transcription factors (proteins containing a DNA‐binding motif termed the paired box) act as regulators of pattern formation and play essential roles during early development and organogenesis. The functions of different Pax genes are largely conserved throughout vertebrate evolution (Monsoro‐Burq, 2015). Pax genes are required for orchestrating proper morphological development of various tissues and organs, as demonstrated by the analysis of the wildtype or targeted mutations of these genes (Dahl et al., 1997; Wiggan et al., 2002). Pax3 is a member of the Pax subfamily that is expressed in various tissues during embryogenesis; its role is particularly well investigated during embryonic myogenesis (Daston et al., 1996; Galli et al., 2008; Joven et al., 2013; Zalc et al., 2015). Moreover, it has been shown that mouse inner ear components with melanogenic fates require Pax3 function (Kim et al., 2014). Pax3 protein is involved in regulating cell aggregation and mesenchymal condensation in vitro (Wiggan et al., 2002). Together with Endoglin, Pax3 plays a role in embryonic angiogenesis (Young et al., 2016). Pax3 mutations in the human are associated with Waardenburg syndrome (type I and type III; Borycki et al., 1999). Pax3 regulates the expression of glial fibrillary acidic protein (GFAP) in the brain glioma stem cells and affects their proliferation and differentiation (Su et al., 2016). In the nervous system, Pax3 regulates the patterning and differentiation of the dorsal neural tube and neural crest (Degenhardt et al., 2010; Monsoro‐Burq, 2015).
In the early neural tube, Pax3 and its homolog Pax7 are expressed in its dorsal part, i.e., in the alar plate. Later in development, Pax3 becomes more broadly expressed in the brain and spinal cord (Goulding et al., 1991; Agoston et al., 2012). Pax3‐mutant mice are characterized by exencephaly, defects in myogenesis, and abnormal differentiation of neural crest cells (Epstein et al., 1991; Conway et al., 1997). Double mutations for Pax3 and Pax7 cause severe exencephaly and spina bifida, as well as defects in spinal commissural neurons (Mansouri and Gruss, 1998). In the developing chicken, Pax3 and Pax7 both are involved in the expression regulation of Meis homebox 2 (Meis2) in the dorsal mesencephalic vesicle (Agoston et al., 2012). Pax3 activity is regulated by hippo signaling in premigratory neural crest cells (Manderfield et al., 2014), and it cooperates with Zic1 to induce neural crest development and differentiation (Milet et al., 2013). Ectopic Pax3 expression in osteogenic Saos‐2 cells results in the formation of cell aggregation with epithelial characteristics (Wiggan et al., 2002). We have reported that Pax3 is involved in neuron differentiation and its overexpression induces ectopic expression of cadherin‐7 (Lin et al., 2016). We also observed that the axons in Pax3‐overexpressing regions seem abnormal and do not project properly compared to the wildtype (Lin et al., 2016).
Spinal commissural neurons are a major class of projection neurons that are located within a dorsal region (dI1 and dI2) of the developing spinal cord (Imondi and Kaprielian, 2001); they stereotypically extend axons ventrally in parallel to the lateral edge of the spinal cord, and then grow ventromedially toward the floor plate when reaching the motor neuron column (Bovolenta and Dodd, 1990). After crossing the midline (floor plate) and entering the marginal zone, they are arranged within highly organized longitudinal tracts to project to distinct targets, thus establishing connections between the two symmetric halves of the nervous system (Imondi and Kaprielian, 2001; Arakawa et al., 2008; Sakai and Kaprielian, 2012). Both Pax3 and Pax7 are expressed in the dI1 and dI2 commissural neurons (Lin et al., 2016).

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