Heparanase 2, mutated in urofacial syndrome, mediates peripheral neural development in Xenopus

N A Roberts,E A Mckenzie,R Thuret,H M Stuart,W G Newman,A S Woolf,E N Hilton

doi:10.1093/hmg/ddu147

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.

Highlights

Urofacial syndrome (UFS; previously Ochoa syndrome; Online Mendelian Inheritance in Man (OMIM) #236730) is an autosomal recessive disease
We recently showed that transcripts for both UFS genes are present in healthy mammalian bladders; heparanase 2 (HPSE2) and LRIG2 proteins were immunodetected in nerve fascicles growing into muscle layers of human foetal bladder walls [7,18]
This study is the first to demonstrate in vivo developmental roles for heparanase 2 in any model organism and is the first to shed light on the pathogenic biological mechanisms underpinning the clinical features of UFS

Summary

Introduction

Urofacial syndrome (UFS; previously Ochoa syndrome; OMIM #236730) is an autosomal recessive disease. It is characterized by incomplete bladder emptying during micturition. UFS is characterized by an abnormal facial expression upon smiling, typically with downturned lateral aspects of the mouth (1 – 4). In families with more than one affected member, existing individuals have sometimes only been designated as having UFS after their more severely affected sibling was diagnosed. The congenital nature of certain aspects of the syndrome is evidenced by the fact that UFS newborns have a distorted expression when crying and, lower urinary tract dysmorphology (e.g. hydronephrosis and an enlarged bladder) can present before birth [7]. At least some clinical features of UFS should be regarded manifestations of abnormal development

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Conclusion