Reduction of cellular sulfation during mouse brain development results in microcephaly marked by neuronal cell death and abnormal neuronal progenitor proliferation

Abstract

ligands of several signalling pathways during development. Notum, a secreted alpha/beta hydrolase, was found to antagonize the signalling of the prototypical Drosophila Wnt, Wingless, by shedding glypicans from the cell surface. Biochemical work demonstrated that a mammalian Notum homologue could induce the release of glypicans by GPI cleavage. In zebrafish, we found three notum genes. One homologue, nom1a, is most closely related to mammalian Notum with respect to protein identity and genomic synteny. The expression of nom1a is dynamic and regulated by Wnt/Beta-Catenin signalling. Overexpression of nom1a at multiple stages of development causes changes in gene expression consistent with Wnt/Beta-Catenin inhibition. Additionally, nom1a expression rescues phenotypes induced by Wnt1 and Wnt8 overexpression, while loss of Nom1a enhances these phenotypes. Using loss and gain of function studies, we have shown that Nom1a is required for the proper patterning of the dorsal neural tube. We have found no evidence that Nom1a inhibits the function of Glypican 4 in Wnt/PCP signalling. In contrast, Glypican 3 is a likely target of Nom1a, as alterations of Gpc3 levels alter the severity of Nom1a-overexpression phenotypes. Our analyses suggest that Nom1a has a surprisingly limited set of targets, and we have identified a novel mechanism restricting Wnt/Beta-Catenin signalling.