Identifying Monosomy 1p36 syndrome as a ciliopathy through exploring the functional role of the ER-Golgi cargoreceptor Rer1p in ciliogenesis in cell models and zebrafish.

Rer1pis a quality control protein mediating the assembly of multimeric complexes during endoplasmic reticulum-to-Golgi transport. We recognized rer1 as the most commonly deleted gene in patients suffering from monosomy 1p36 microdeletion syndrome. To study its physiological role and its potential contribution to this disease, we chose the zebrafish embryo as a model system. We show that Rer1p is highly expressed in ciliated cells/organs and its downregulation results in a phenotype strongly reminiscent of a ciliopathy. As zebrafish morphants recapitulate several major clinical features of monosomy 1p36, we hypothesize the monosomy being an as yet unrecognized ciliopathy and imply a role for Rer1p in ciliogenesis. To test this we will perform an indepth correlative phenotypic study of zebrafish morphants with respect to monosomy 1p36 and ciliopathies. Secondly, using several cellular models inclusing patients'cells, we will explore underlying mechanisms by which Rer1p contributes to the formation/maintenance of cilia. Finally, the establishment of a Rer1p knockdown model will provide a first means to screen for modifiers of Rer1p expression. Our study implicates for the first time a component of the early secretory pathway in ciliogenesis and exploring its function will therefore have implications both for cell biology, as well as disease.

Keywords:Zebrafish, Cilia, ER-Golgi

Disciplines:Systems biology, Medical biochemistry and metabolism, Biochemistry and metabolism, Physiology, Animal biology, Genetics