Huntingtin function during zebrafish (Danio rerio) development.

Abstract

Huntington’s disease shares a common molecular basis with eight other neurodegenerative diseases: expansion of an existing polyglutamine tract. In each case, this repeat tract occurs within otherwise unrelated proteins. These proteins show widespread and overlapping patterns of expression in the brain and yet the diseases are distinguished by neurodegeneration in a specific subset of neurons that are most sensitive to the mutation. It has therefore been proposed that expansion of the polyglutamine region in these genes may result in perturbation of the normal function of the respective proteins, and that this perturbation in some way contributes to the neuronal specificity of these diseases. The normal functions of these proteins have therefore become a focus of investigation as potential pathogenic pathways. Here, synthetic antisense morpholinos have been used to inhibit the translation of huntingtin protein during early zebrafish development. The results obtained show the effects of huntingtin loss-of-function on the developing nervous system, including distinct defects in morphology of the lateral line neuromasts, olfactory placode and branchial arches. The potential common origins of these defects were explored, revealing impaired formation of the anterior-most region of the neural plate as indicated by reduced pre-placodal and telencephalic gene expression with no effect on mid- or hindbrain formation. These investigations demonstrate a specific ‘rate-limiting’ role for huntingtin in formation of the telencephalon and the pre-placodal region, and differing levels of requirement for huntingtin function in specific nerve cell types.