title: Heparanase 2, mutated in urofacial syndrome, mediates peripheral neural development in Xenopus.
abstract: Urofacial syndrome (UFS; previously Ochoa syndrome) is an autosomal recessive disease characterized by incomplete bladder emptying during micturition. This is associated with a dyssynergia in which the urethral walls contract at the same time as the detrusor smooth muscle in the body of the bladder. UFS is also characterized by an abnormal facial expression upon smiling, and bilateral weakness in the distribution of the facial nerve has been reported. Biallelic mutations in HPSE2 occur in UFS. This gene encodes heparanase 2, a protein which inhibits the activity of heparanase. Here, we demonstrate, for the first time, an in vivo developmental role for heparanase 2. We identified the Xenopus orthologue of heparanase 2 and showed that the protein is localized to the embryonic ventrolateral neural tube where motor neurons arise. Morpholino-induced loss of heparanase 2 caused embryonic skeletal muscle paralysis, and morphant motor neurons had aberrant morphology including less linear paths and less compactly-bundled axons than normal. Biochemical analyses demonstrated that loss of heparanase 2 led to upregulation of fibroblast growth factor 2/phosphorylated extracellular signal-related kinase signalling and to alterations in levels of transcripts encoding neural- and muscle-associated molecules. Thus, a key role of heparanase 2 is to buffer growth factor signalling in motor neuron development. These results shed light on the pathogenic mechanisms underpinning the clinical features of UFS and support the contention that congenital peripheral neuropathy is a key feature of this disorder.
authors.affiliation: Centre for Genomic Medicine and Centre for Paediatrics and Child Health, Institute of Human Development, Faculty of Medical and Human Sciences.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Roberts
authors.affiliation: Centre for Paediatrics and Child Health, Institute of Human Development, Faculty of Medical and Human Sciences.
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Woolf
authors.affiliation: Centre for Genomic Medicine and.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Stuart
authors.affiliation: Developmental Biology and.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Thuret
authors.affiliation: Protein Expression Facility, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Edward A
authors.initials: EA
authors.lastname: McKenzie
authors.affiliation: Centre for Genomic Medicine and.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Centre for Genomic Medicine and Centre for Paediatrics and Child Health, Institute of Human Development, Faculty of Medical and Human Sciences, emma.hilton@manchester.ac.uk.
authors.forename: Emma N
authors.initials: EN
authors.lastname: Hilton
mesh_terms: D000818:Animals; D019066:Facies; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000196:embryology / Q000378:metabolism; D009154:Mutation; D054259:Neural Tube / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D014570:Urologic Diseases / Q000235:genetics; D014981:Xenopus; D019892:eIF-2 Kinase / Q000378:metabolism; D000099175:Heparanase
chemical_list: D016222:Fibroblast Growth Factor 2; D005966:Glucuronidase; D019892:eIF-2 Kinase; D000099175:Heparanase