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Background  Notch signalling plays a central role in the mechanisms regulating neuronal differentiation in the vertebrate nervous system. The transcriptional repressors encoded by  Hes  genes are the main effectors of this pathway, acting in neural progenitors during the lateral inhibition process to repress proneural genes and inhibit differentiation. However,  Hes6  genes seem to behave differently: they are expressed in differentiating neurons and facilitate the activity of proneural genes in promoting neurogenesis. Still, the molecular mechanisms underlying this unique function of  Hes6  genes are not yet understood.    Methodology/Principal Findings  Here, we identify two subgroups of  Hes6  genes that seem conserved in most vertebrate species and characterize a novel  Hes6  gene in chicken: c Hes6-1 . The embryonic expression pattern of c Hes6-1  suggests roles for this gene in the formation of the pancreas, nervous system and in the generation of body asymmetry. We show that c Hes6-1  is negatively regulated by Notch signalling in the developing embryonic spinal cord and in pancreatic progenitors, but requires Notch for the observed asymmetric expression at the lateral mesoderm. Functional studies by ectopic expression in the chick embryonic neural tube revealed that cHES6-1 up-regulates the expression of c Delta1  and c Hes5  genes, in contrast with overexpression of cHES6-2, which represses the same genes. We show that this activity of cHES6-2 is dependent on its capacity to bind DNA and repress transcription, while cHES6-1 seems to function by sequestering other HES proteins and inhibit their activity as transcriptional repressors.    Conclusions/Significance  Our results indicate that the two chick HES6 proteins act at different phases of neuronal differentiation, contributing to the progression of neurogenesis by different mechanisms: while cHES6-2 represses the transcription of  Hes  genes, cHES6-1 acts later, sequestering HES proteins. Together, the two cHES6 proteins progressively shut down the Notch-mediated progenitor program and ensure that neuronal differentiation can proceed.

HES6-1 and HES6-2 Function through Different Mechanisms during Neuronal Differentiation