Abstract
The advent of the ocular and nervous system in metazoan evolution coincides with the diversification of a single ancestral paired box (Pax) gene into Pax6, Pax6(5a), and Pax2. To investigate the role of these Pax genes in neural development, we have generated an allelic series of knock-in models at the Pax6 locus. We showed that although Pax6(5a) and Pax2 could not replace Pax6 for its autoregulation in lens induction or for neural differentiation in retina, Pax6(5a) was sufficient for corneal-lenticular detachment. In brain development, cell proliferation in the cerebral cortex and dorsoventral patterning of the telencephalon and neural tube were partially rescued in either knock-in mutant. Contrary to the previous belief, our genetic studies showed that the Pax6 isoform Pax6(5a) could potentially play a role in neuronal differentiation in brain development. Importantly, Pax2 showed greater rescue efficiency than Pax6(5a) in the telencephalon even though the latter was identical to Pax6 outside the paired domain. In studying Ngn2, a Pax6 direct target gene in telencephalon, we showed that the level of Ngn2 expression correlated with the in vitro binding of Pax2, Pax6, and Pax6(5a) paired domain on its enhancer. Our results show that Pax6 is uniquely required for eye development, but in brain development, Pax6 can be functionally substituted by related Pax family genes that share a similar paired domain binding specificity.
Highlights
Pax6, Pax6(5a), and Pax2 are derived from a common Pax2-like ancestral gene
Our results show that Pax6 is uniquely required for eye development, but in brain development, Pax6 can be functionally substituted by related paired box (Pax) family genes that share a similar paired domain binding specificity
In both the Pax65a/5a and Pax6Pax2/Pax2 mutants, lens development was abolished because lens induction never occurred
Summary
Pax6(5a), and Pax are derived from a common Pax2-like ancestral gene. Results: Pax6(5a) and Pax can partially substitute for Pax in neural development. Our results show that Pax is uniquely required for eye development, but in brain development, Pax can be functionally substituted by related Pax family genes that share a similar paired domain binding specificity. Pax expression in forebrain is primarily restricted to the dorsal telencephalon where Pax activates the dorsal telencephalic transcription factor Ngn expression to prevent the expansion of ventral transcription factor Mash while maintaining the boundary structures to restrict cell migration [18, 19] In addition to these neural patterning defects, the Pax6-null progenitors in the dorsal telencephalon present with cell cycle and migratory abnormalities, resulting in a thinner cortical plate (20 –23). Even in the eye, Pax and Pax expressions quickly diverge through mutual repression to control optic stalk and neural retina development, respectively [33] It remains unclear how these two transcriptional regulators that share an almost identical consensus PD binding sequence can have sometimes redundant but often divergent functions in embryogenesis. Whereas the entire Pax protein is necessary for eye development, the binding specificity of the PD is largely sufficient to determine the functional specificity of Pax, Pax, and Pax6(5a) in forebrain and neural tube development
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