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• W2890130836 abstract "In mammals, the tenascin family of extracellular matrix (ECM) glycoproteins comprises four subgroups (TNC; tenascin C, formerly called ‘cytotactin’) tenascin R (TNR; ‘restrictin’), tenascin X (TNX; ‘flexilin’) and tenascin W (TNW, also called tenascin N; (Bristow et al. 2005; Valcourt et al. 2015). All share a common general structure, but differences in expression patterns during both development and adulthood have led to the suggestion that physiological, and possibly pathophysiological, differences exist in the functions of each of these family members. In general, however, ECM glycoproteins perform critical architectural and structural roles as seen by the connective tissues disorders that result from loss-of-function mutations, including Ehlers-Danlos syndrome (EDS), which is associated with the loss of TNX. Indeed, TNX deficiency is now recognized as a distinct subgroup (classical-like EDS) within the EDS spectrum of generalized joint hypermobility disorders (Bristow et al. 2005). In the current issue of The Journal of Physiology, Aktar et al. (2018) report the novel, and exciting, finding that TNX is also expressed in specific neuronal populations within both the human and mouse gastrointestinal (GI) tract, suggesting potentially new and undiscovered roles for ECM glycoproteins in the control and regulation of gut functions. In the almost three decades since its initial discovery as a glycoprotein associated with collagen fibrils, TNX is now known to perform additional roles as both a matricellular protein modulating cell adhesion and a modulator of signalling pathways (Valcourt et al. 2015). While expressed ubiquitously in late embryonic development, in adulthood TNX mRNA has a more restricted distribution, but is expressed at high levels in the GI tract and pancreas (Valcourt et al. 2015). Perhaps unsurprisingly, therefore, multiple prospective and retrospective studies have implied that a significant association exists between disorders associated with TNX deficiency and functional GI disorders including gastro-oesophageal reflux disease (GORD), delayed gastric emptying and postprandial distress syndrome, pain and irritable bowel syndrome (IBS) (summarized in Botrus et al. 2018). ECM proteins, including the tenascins, are clearly critical for gut wall infrastructure; until now, the characteristic connective tissues abnormalities that occur in response to TNX deficiency were assumed to be responsible for the observed increased compliance and stretch capacity of GI muscle. In the present manuscript, however, Aktar et al. report that, while TNX expression is certainly dense within the GI tract, it is found exclusively within enteric neurones. Not only may TNX have potentially unique roles in the regulation of GI functions, it raises the possibility that the dysregulation of mechanosensitivity, decreased pain thresholds and motility disorders reported by TNX-deficiency patients may be due to neural, rather than muscular, dysfunction (Aktar et al. 2018; Botrus et al. 2018). Using immunohistochemical methods, Aktar et al. demonstrated that, while TNC was present within gut wall connective tissue, TNX expression was restricted, somewhat surprisingly, to enteric neurones. In fact, TNX was localized predominantly in cholinergic (choline acetyltransferase, ChAT) and calretenin-positive neurones within both the myenteric and submucosal plexuses. The reduced colonic contractile activity observed in TNX knock-out mice confirmed its potential involvement in the neural regulation of GI contractile activity. Notably, altered bowel habits (both constipation and diarrhoea) were reported by a significant proportion of the genetically confirmed TNX-deficient patients investigated in the present study. Interestingly, while TNX has not been proposed to play any significant role in peripheral nociception, the authors also revealed a surprising increase in sprouting of the fibres immunostained for the nociceptive marker, calcitonin gene-related peptide (CGRP) in the colonic mucosa of TNX knock-out mice. While colonic compliance was not affected, baseline splanchnic afferent nerve activity was increased as was the response to distension, the implication being that TNX deficiency is associated with an overall increase in colonic afferent sensitivity and, potentially, visceral pain and hyperalgesia. Indeed, increased abdominal pain was reported by almost two-thirds of TNX-deficient patients in the present study. The mechanism by which TNX regulates afferent sensitivity remains to be elucidated, although it should be noted that TNX has anti-adhesive properties and may inhibit neurite development and outgrowth, while other members of the tenascin family, notably TNC and TNR, modulate neural growth and regeneration through their actions as both repellent and migration guidance molecules (Valcourt et al. 2015). Furthermore, TNR in particular is enriched within peri-neuronal nets (PNNs), ECM structures within the adult central nervous system that surround and envelop the soma, proximal dendrites and initial axon segment of neurons, forming a net-like structure that modulates, regulates, and integrates synaptic plasticity, learning and memory, and the response to injury and inflammation (Song & Dityatev, 2018). The possible involvement and functional role of tenascins, including TNX, within an enteric PNN (if such a structure even exists) remains to be investigated, but the potential for altered neuronal plasticity, as well as altered responses to GI insult and inflammation, raises intriguing questions surrounding further roles for these ECM glycoproteins in health and disease. While once considered purely architectural, tenascins quite clearly fulfil multiple non-structural roles. The recent localization of TNX within enteric neurons expands the capacity of these glycoproteins to include the neural control and modulation of GI functions (Aktar et al. 2018). The well-recognized GI co-morbidities of tenascin-deficiency disorders such as EDS behooves both clinicians and translational and basic researchers to pay more attention to their structure, function and role in physiology and pathophysiology. The author has no competing interests. Sole author. Supported by NIH NIDDK grant DK111667." @default.
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• W2890130836 date "2018-08-31" @default.
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• W2890130836 title "Extracellular matrix proteins in the gastrointestinal tract: more than a supporting role" @default.
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