The extracellular matrix glycoprotein tenascin-X regulates peripheral sensory and motor neurones

Rubina Aktar; Madusha Peiris; Asma Fikree; Vincent Cibert-Goton; Maxim Walmsley; Iain R. Tough; Paulo Watanabe; Eduardo J.A. Araujo; Sahar D. Mohammed; Jean Marie Delalande; David C. Bulmer; S. Mark Scott; Helen M. Cox; Nicol C. Voermans; Qasim Aziz; L. Ashley Blackshaw

doi:10.1113/JP276300

The extracellular matrix glycoprotein tenascin-X regulates peripheral sensory and motor neurones

Rubina Aktar, Madusha Peiris, Asma Fikree, Vincent Cibert-Goton, Maxim Walmsley, Iain R. Tough, Paulo Watanabe, Eduardo J.A. Araujo, Sahar D. Mohammed, Jean Marie Delalande, David C. Bulmer, S. Mark Scott, Helen M. Cox, Nicol C. Voermans, Qasim Aziz, L. Ashley Blackshaw^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

34 Citations (Scopus)

Abstract

Key points: Tenascin-X (TNX) is an extracellular matrix glycoprotein with anti-adhesive properties in skin and joints. Here we report the novel finding that TNX is expressed in human and mouse gut tissue where it is exclusive to specific subpopulations of neurones. Our studies with TNX-deficient mice show impaired defecation and neural control of distal colonic motility that can be rescued with a 5-HT₄ receptor agonist. However, colonic secretion is unchanged. They are also susceptible to internal rectal intussusception. Colonic afferent sensitivity is increased in TNX-deficient mice. Correspondingly, there is increased density of and sensitivity of putative nociceptive fibres in TNX-deficient mucosa. A group of TNX-deficient patients report symptoms highly consistent with those in the mouse model. These findings suggest TNX plays entirely different roles in gut to non-visceral tissues – firstly a role in enteric motor neurones and secondly a role influencing nociceptive sensory neurones Studying further the mechanisms by which TNX influences neuronal function will lead to new targets for future treatment. Abstract: The extracellular matrix (ECM) is not only an integral structural molecule, but is also critical for a wide range of cellular functions. The glycoprotein tenascin-X (TNX) predominates in the ECM of tissues like skin and regulates tissue structure through anti-adhesive interactions with collagen. Monogenic TNX deficiency causes painful joint hypermobility and skin hyperelasticity, symptoms characteristic of hypermobility Ehlers Danlos syndrome (hEDS). hEDS patients also report consistently increased visceral pain and gastrointestinal (GI) dysfunction. We investigated whether there is a direct link between TNX deficiency and GI pain or motor dysfunction. We set out first to learn where TNX is expressed in human and mouse, then determine how GI function, specifically in the colon, is disordered in TNX-deficient mice and humans of either sex. In human and mouse tissue, TNX was predominantly associated with cholinergic colonic enteric neurones, which are involved in motor control. TNX was absent from extrinsic nociceptive peptidergic neurones. TNX-deficient mice had internal rectal prolapse and a loss of distal colonic contractility which could be rescued by prokinetic drug treatment. TNX-deficient patients reported increased sensory and motor GI symptoms including abdominal pain and constipation compared to controls. Despite absence of TNX from nociceptive colonic neurones, neuronal sprouting and hyper-responsiveness to colonic distension was observed in the TNX-deficient mice. We conclude that ECM molecules are not merely support structures but an integral part of the microenvironment particularly for specific populations of colonic motor neurones where TNX exerts functional influences.

Original language	English
Pages (from-to)	4237-4251
Number of pages	15
Journal	Journal of Physiology
Volume	596
Issue number	17
DOIs	https://doi.org/10.1113/JP276300
Publication status	Published - 1 Sept 2018

Keywords

Colonic hypersensitivity
Colonic motility
Enteric neurones

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1113/JP276300

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Aktar, R., Peiris, M., Fikree, A., Cibert-Goton, V., Walmsley, M., Tough, I. R., Watanabe, P., Araujo, E. J. A., Mohammed, S. D., Delalande, J. M., Bulmer, D. C., Scott, S. M., Cox, H. M., Voermans, N. C., Aziz, Q., & Blackshaw, L. A. (2018). The extracellular matrix glycoprotein tenascin-X regulates peripheral sensory and motor neurones. Journal of Physiology, 596(17), 4237-4251. https://doi.org/10.1113/JP276300

@article{6d47371607aa4147a0d687eab91d09cf,

title = "The extracellular matrix glycoprotein tenascin-X regulates peripheral sensory and motor neurones",

abstract = "Key points: Tenascin-X (TNX) is an extracellular matrix glycoprotein with anti-adhesive properties in skin and joints. Here we report the novel finding that TNX is expressed in human and mouse gut tissue where it is exclusive to specific subpopulations of neurones. Our studies with TNX-deficient mice show impaired defecation and neural control of distal colonic motility that can be rescued with a 5-HT4 receptor agonist. However, colonic secretion is unchanged. They are also susceptible to internal rectal intussusception. Colonic afferent sensitivity is increased in TNX-deficient mice. Correspondingly, there is increased density of and sensitivity of putative nociceptive fibres in TNX-deficient mucosa. A group of TNX-deficient patients report symptoms highly consistent with those in the mouse model. These findings suggest TNX plays entirely different roles in gut to non-visceral tissues – firstly a role in enteric motor neurones and secondly a role influencing nociceptive sensory neurones Studying further the mechanisms by which TNX influences neuronal function will lead to new targets for future treatment. Abstract: The extracellular matrix (ECM) is not only an integral structural molecule, but is also critical for a wide range of cellular functions. The glycoprotein tenascin-X (TNX) predominates in the ECM of tissues like skin and regulates tissue structure through anti-adhesive interactions with collagen. Monogenic TNX deficiency causes painful joint hypermobility and skin hyperelasticity, symptoms characteristic of hypermobility Ehlers Danlos syndrome (hEDS). hEDS patients also report consistently increased visceral pain and gastrointestinal (GI) dysfunction. We investigated whether there is a direct link between TNX deficiency and GI pain or motor dysfunction. We set out first to learn where TNX is expressed in human and mouse, then determine how GI function, specifically in the colon, is disordered in TNX-deficient mice and humans of either sex. In human and mouse tissue, TNX was predominantly associated with cholinergic colonic enteric neurones, which are involved in motor control. TNX was absent from extrinsic nociceptive peptidergic neurones. TNX-deficient mice had internal rectal prolapse and a loss of distal colonic contractility which could be rescued by prokinetic drug treatment. TNX-deficient patients reported increased sensory and motor GI symptoms including abdominal pain and constipation compared to controls. Despite absence of TNX from nociceptive colonic neurones, neuronal sprouting and hyper-responsiveness to colonic distension was observed in the TNX-deficient mice. We conclude that ECM molecules are not merely support structures but an integral part of the microenvironment particularly for specific populations of colonic motor neurones where TNX exerts functional influences.",

keywords = "Colonic hypersensitivity, Colonic motility, Enteric neurones",

author = "Rubina Aktar and Madusha Peiris and Asma Fikree and Vincent Cibert-Goton and Maxim Walmsley and Tough, {Iain R.} and Paulo Watanabe and Araujo, {Eduardo J.A.} and Mohammed, {Sahar D.} and Delalande, {Jean Marie} and Bulmer, {David C.} and Scott, {S. Mark} and Cox, {Helen M.} and Voermans, {Nicol C.} and Qasim Aziz and Blackshaw, {L. Ashley}",

year = "2018",

month = sep,

day = "1",

doi = "10.1113/JP276300",

language = "English",

volume = "596",

pages = "4237--4251",

journal = "Journal of Physiology",

issn = "0022-3751",

publisher = "Wiley",

number = "17",

}

Aktar, R, Peiris, M, Fikree, A, Cibert-Goton, V, Walmsley, M, Tough, IR, Watanabe, P, Araujo, EJA, Mohammed, SD, Delalande, JM, Bulmer, DC, Scott, SM, Cox, HM, Voermans, NC, Aziz, Q & Blackshaw, LA 2018, 'The extracellular matrix glycoprotein tenascin-X regulates peripheral sensory and motor neurones', Journal of Physiology, vol. 596, no. 17, pp. 4237-4251. https://doi.org/10.1113/JP276300

TY - JOUR

T1 - The extracellular matrix glycoprotein tenascin-X regulates peripheral sensory and motor neurones

AU - Aktar, Rubina

AU - Peiris, Madusha

AU - Fikree, Asma

AU - Cibert-Goton, Vincent

AU - Walmsley, Maxim

AU - Tough, Iain R.

AU - Watanabe, Paulo

AU - Araujo, Eduardo J.A.

AU - Mohammed, Sahar D.

AU - Delalande, Jean Marie

AU - Bulmer, David C.

AU - Scott, S. Mark

AU - Cox, Helen M.

AU - Voermans, Nicol C.

AU - Aziz, Qasim

AU - Blackshaw, L. Ashley

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Key points: Tenascin-X (TNX) is an extracellular matrix glycoprotein with anti-adhesive properties in skin and joints. Here we report the novel finding that TNX is expressed in human and mouse gut tissue where it is exclusive to specific subpopulations of neurones. Our studies with TNX-deficient mice show impaired defecation and neural control of distal colonic motility that can be rescued with a 5-HT4 receptor agonist. However, colonic secretion is unchanged. They are also susceptible to internal rectal intussusception. Colonic afferent sensitivity is increased in TNX-deficient mice. Correspondingly, there is increased density of and sensitivity of putative nociceptive fibres in TNX-deficient mucosa. A group of TNX-deficient patients report symptoms highly consistent with those in the mouse model. These findings suggest TNX plays entirely different roles in gut to non-visceral tissues – firstly a role in enteric motor neurones and secondly a role influencing nociceptive sensory neurones Studying further the mechanisms by which TNX influences neuronal function will lead to new targets for future treatment. Abstract: The extracellular matrix (ECM) is not only an integral structural molecule, but is also critical for a wide range of cellular functions. The glycoprotein tenascin-X (TNX) predominates in the ECM of tissues like skin and regulates tissue structure through anti-adhesive interactions with collagen. Monogenic TNX deficiency causes painful joint hypermobility and skin hyperelasticity, symptoms characteristic of hypermobility Ehlers Danlos syndrome (hEDS). hEDS patients also report consistently increased visceral pain and gastrointestinal (GI) dysfunction. We investigated whether there is a direct link between TNX deficiency and GI pain or motor dysfunction. We set out first to learn where TNX is expressed in human and mouse, then determine how GI function, specifically in the colon, is disordered in TNX-deficient mice and humans of either sex. In human and mouse tissue, TNX was predominantly associated with cholinergic colonic enteric neurones, which are involved in motor control. TNX was absent from extrinsic nociceptive peptidergic neurones. TNX-deficient mice had internal rectal prolapse and a loss of distal colonic contractility which could be rescued by prokinetic drug treatment. TNX-deficient patients reported increased sensory and motor GI symptoms including abdominal pain and constipation compared to controls. Despite absence of TNX from nociceptive colonic neurones, neuronal sprouting and hyper-responsiveness to colonic distension was observed in the TNX-deficient mice. We conclude that ECM molecules are not merely support structures but an integral part of the microenvironment particularly for specific populations of colonic motor neurones where TNX exerts functional influences.

AB - Key points: Tenascin-X (TNX) is an extracellular matrix glycoprotein with anti-adhesive properties in skin and joints. Here we report the novel finding that TNX is expressed in human and mouse gut tissue where it is exclusive to specific subpopulations of neurones. Our studies with TNX-deficient mice show impaired defecation and neural control of distal colonic motility that can be rescued with a 5-HT4 receptor agonist. However, colonic secretion is unchanged. They are also susceptible to internal rectal intussusception. Colonic afferent sensitivity is increased in TNX-deficient mice. Correspondingly, there is increased density of and sensitivity of putative nociceptive fibres in TNX-deficient mucosa. A group of TNX-deficient patients report symptoms highly consistent with those in the mouse model. These findings suggest TNX plays entirely different roles in gut to non-visceral tissues – firstly a role in enteric motor neurones and secondly a role influencing nociceptive sensory neurones Studying further the mechanisms by which TNX influences neuronal function will lead to new targets for future treatment. Abstract: The extracellular matrix (ECM) is not only an integral structural molecule, but is also critical for a wide range of cellular functions. The glycoprotein tenascin-X (TNX) predominates in the ECM of tissues like skin and regulates tissue structure through anti-adhesive interactions with collagen. Monogenic TNX deficiency causes painful joint hypermobility and skin hyperelasticity, symptoms characteristic of hypermobility Ehlers Danlos syndrome (hEDS). hEDS patients also report consistently increased visceral pain and gastrointestinal (GI) dysfunction. We investigated whether there is a direct link between TNX deficiency and GI pain or motor dysfunction. We set out first to learn where TNX is expressed in human and mouse, then determine how GI function, specifically in the colon, is disordered in TNX-deficient mice and humans of either sex. In human and mouse tissue, TNX was predominantly associated with cholinergic colonic enteric neurones, which are involved in motor control. TNX was absent from extrinsic nociceptive peptidergic neurones. TNX-deficient mice had internal rectal prolapse and a loss of distal colonic contractility which could be rescued by prokinetic drug treatment. TNX-deficient patients reported increased sensory and motor GI symptoms including abdominal pain and constipation compared to controls. Despite absence of TNX from nociceptive colonic neurones, neuronal sprouting and hyper-responsiveness to colonic distension was observed in the TNX-deficient mice. We conclude that ECM molecules are not merely support structures but an integral part of the microenvironment particularly for specific populations of colonic motor neurones where TNX exerts functional influences.

KW - Colonic hypersensitivity

KW - Colonic motility

KW - Enteric neurones

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U2 - 10.1113/JP276300

DO - 10.1113/JP276300

M3 - Article

AN - SCOPUS:85050829904

SN - 0022-3751

VL - 596

SP - 4237

EP - 4251

JO - Journal of Physiology

JF - Journal of Physiology

IS - 17

ER -

The extracellular matrix glycoprotein tenascin-X regulates peripheral sensory and motor neurones

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Keywords

UN SDGs

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