Heparanase 2, mutated in urofacial syndrome, mediates peripheral neural development in XenopusCitation formats

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Heparanase 2, mutated in urofacial syndrome, mediates peripheral neural development in Xenopus. / Roberts, Neil; Woolf, Adrian S.; Stuart, Helen M.; Thuret, Raphaël; McKenzie, Edward A.; Newman, William G.; Hilton, Emma N.

In: Human Molecular Genetics, Vol. 23, No. 16, ddu147, 08.2014, p. 4302-4314.

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@article{04ad6565271e481e9e95b12dac2d54b1,
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.",
keywords = "HPSE2, Urofacial, Nerve, Xenopus",
author = "Neil Roberts and Woolf, {Adrian S.} and Stuart, {Helen M.} and Rapha{\"e}l Thuret and McKenzie, {Edward A.} and Newman, {William G.} and Hilton, {Emma N.}",
year = "2014",
month = aug,
doi = "10.1093/hmg/ddu147",
language = "English",
volume = "23",
pages = "4302--4314",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "16",

}

RIS

TY - JOUR

T1 - Heparanase 2, mutated in urofacial syndrome, mediates peripheral neural development in Xenopus

AU - Roberts, Neil

AU - Woolf, Adrian S.

AU - Stuart, Helen M.

AU - Thuret, Raphaël

AU - McKenzie, Edward A.

AU - Newman, William G.

AU - Hilton, Emma N.

PY - 2014/8

Y1 - 2014/8

N2 - 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.

AB - 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.

KW - HPSE2

KW - Urofacial

KW - Nerve

KW - Xenopus

U2 - 10.1093/hmg/ddu147

DO - 10.1093/hmg/ddu147

M3 - Article

C2 - 24691552

VL - 23

SP - 4302

EP - 4314

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 16

M1 - ddu147

ER -