Functional equivalence of Brn3 POU-domain transcription factors in mouse retinal neurogenesis

Abstract

POU-domain transcription factors play essential roles in cell proliferation and differentiation. Previous studies have shown that targeted deletion of each of the three POU-domain Brn3 factors in mice leads to the developmental failure and apoptosis of a unique set of sensory neurons in retina, dorsal root ganglia, trigeminal ganglia and inner ear. The specific defects associated with the removal of each Brn3 gene closely reflect their characteristic spatiotemporal expression patterns. Nevertheless, it remains elusive whether Brn3 factors are functionally equivalent and act through a common molecular mechanism to regulate the development and survival of these sensory neurons. By knocking-in Brn3a (Brn3aki) into the Brn3b locus, we showed here that Brn3aki was expressed in a spatiotemporal manner identical to that of endogenous Brn3b. In addition, Brn3aki functionally restored the normal development and survival of retinal ganglion cells (RGCs) in the absence of Brn3b and fully reinstated the early developmental expression profiles of Brn3b downstream target genes in retina. These results indicate that Brn3 factors are functionally equal and that their unique roles in neurogenesis are determined by the distinctive Brn3 spatiotemporal expression patterns.