Autoregulation and multiple enhancers control Math1 expression in the developing nervous system

Development of the vertebrate nervous system requires the actions of transc ription factors that establish regional domains of gene expression, which r esults in the generation of diverse neuronal cell types, MATH1, a transcrip tion factor of the bHLH class, is expressed during development of the nervo us system in multiple neuronal domains, including the dorsal neural tube, t he EGL of the cerebellum and the hair cells of the vestibular and auditory systems. MATH1 is essential for proper development of the granular layer of the cerebellum and the hair cells of the cochlear and vestibular systems, as shown in mice carrying a targeted disruption of Mathl. Previously, we sh owed that 21 kb of sequence flanking the Math1-coding region is sufficient for Math1 expression in transgenic mice. Here we identify two discrete sequ ences within the 21 kb region that are conserved between mouse and human, a nd are sufficient for driving a lacZ reporter gene in these domains of Math 1 expression in transgenic mice. The two identified enhancers, while dissim ilar in sequence, appear to have redundant activities in the different Math 1 expression domains except the spinal neural tube. The regulatory mechanis ms for each of the diverse Math1 expression domains are tightly linked, as separable regulatory elements for any given domain of Math1 expression were not found, suggesting that a common regulatory mechanism controls these ap parently unrelated domains of expression. In addition, we demonstrate a rol e for autoregulation in controlling the activity of the Math1 enhancer, thr ough an essential E-box consensus binding site.