Abstract

Congenital disorder of glycosylation type IIc (CDG IIc) is characterized by mental retardation, slowed growth and severe immunodeficiency, attributed to the lack of fucosylated glycoproteins. While impaired Notch signaling has been implicated in some aspects of CDG IIc pathogenesis, the molecular and cellular mechanisms remain poorly understood. We have identified a zebrafish mutant slytherin (srn), which harbors a missense point mutation in GDP-mannose 4,6 dehydratase (GMDS), the rate-limiting enzyme in protein fucosylation, including that of Notch. Here we report that some of the mechanisms underlying the neural phenotypes in srn and in CGD IIc are Notch-dependent, while others are Notch-independent. We show, for the first time in a vertebrate in vivo, that defects in protein fucosylation leads to defects in neuronal differentiation, maintenance, axon branching, and synapse formation. Srn is thus a useful and important vertebrate model for human CDG IIc that has provided new insights into the neural phenotypes that are hallmarks of the human disorder and has also highlighted the role of protein fucosylation in neural development.

Highlights

  • Congenital disorder of glycosylation, type IIc (CDG IIc), known as leukocyte adhesion deficiency II (LAD II) or RambamHasharon syndrome (RHS), is an autosomal recessive syndrome, characterized by recurrent infections, persistent leukocytosis, severe mental retardation and slowed growth [1,2]

  • To further assess whether Notch-Delta signaling is deficient in srn mutants, we examined the expression of several Notch effector genes, including hes5, her4 and heyl as direct readout of Notch transcriptional activation, using real time quantitative RT-PCR and in situ hybridization. mib embryos display a strong reduction in Notch signaling [13] and hes5, her4 and heyl were collectively shown to be reduced in mib mutant fish and/or mice [35,36,37,38,39]

  • We report that the srn mutation causes a loss of GMDS function, leading to a severe reduction in protein fucosylation, including that of Notch among many others

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Summary

Introduction

Congenital disorder of glycosylation, type IIc (CDG IIc), known as leukocyte adhesion deficiency II (LAD II) or RambamHasharon syndrome (RHS), is an autosomal recessive syndrome, characterized by recurrent infections, persistent leukocytosis, severe mental retardation and slowed growth [1,2]. The gene responsible for CDG IIc has been identified as GDP-fucose transporter (FUCT1) [3,4], which translocates GDP-fucose from the cytosol into the Golgi lumen for fucosyltransferase-catalyzed reactions during the modification of glycans. Several animal models have been generated to study the pathogenesis of CDG IIc: FX locus null mice, lacking an enzyme in the de novo GDP-fucose synthesis pathway [5], Gfr (homologous to FUCT1) null flies [6] and Fuct null mice [7]. Gfr null flies display Notch-like phenotypes during wing development and reduced Notch fucosylation, suggesting that Notch deficiency may be responsible for some of the developmental defects in CDG IIc patients [6]. Despite the neurodevelopmental and cognitive dysfunction prominent in CDG IIc patients, the anatomical, cellular and molecular abnormalities within the nervous system have not been well documented, and the mechanisms underlying this and other neural phenotypes remain unexplored

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