CONTROL OF NORADRENERGIC DIFFERENTIATION AND PHOX2A EXPRESSION BY MASH1 IN THE CENTRAL AND PERIPHERAL NERVOUS-SYSTEM

Mash1, a mammalian homologue of the Drosophila proneural genes of the achaete-scute complex, is transiently expressed throughout the develop ing peripheral autonomic nervous system and in subsets of cells in the neural tube, In the mouse, targeted mutation of Mash1 has revealed a role in the development of parts of the autonomic nervous system and o f olfactory neurons, but no discernible phenotype in the brain has bee n reported, Here, we show that the adrenergic and noradrenergic centre s of the brain are missing in Mash1 mutant embryos, whereas most other brainstem nuclei are preserved, Indeed, the present data together wit h the previous results show that, except in cranial sensory ganglia, M ash1 function is essential for the development of all central and peri pheral neurons that express noradrenergic traits transiently or perman ently, In particular, we show that, in the absence of MASH1, these neu rons fail to initiate expression of the noradrenaline biosynthetic enz yme dopamine beta-hydroxylase. We had previously shown that all these neurons normally express the homeodomain transcription factor Phox2a, a positive regulator of the dopamine beta-hydroxylase gene and that a subset of them depend on it for their survival, We now report that exp ression of Phox2a is abolished or massively altered in the Mash1(-/-) mutants, both in the noradrenergic centres of the brain and in periphe ral autonomic ganglia. These results suggest that MASH1 controls norad renergic differentiation at least in part by controlling expression of Phox2a and point to fundamental homologies in the genetic circuits th at determine the noradrenergic phenotype in the central and peripheral nervous system.