Myo5b knockout mice as a model of microvillus inclusion disease

Cartón-García, Fernando; Overeem, Arend W.; Nieto, Rocío; Bazzocco, Sarah; Dopeso, Higinio; Macaya, Irati; Bilić, Josipa; Landolfi, Stefania; Hernández-Losa, Javier; Schwartz, Simó; Cajal, Santiago Ramón y; IJzendoorn, Sven C. D. van; Arango, Diego

doi:10.1038/srep12312

Cited by 54 publications

(59 citation statements)

References 27 publications

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“…Previous studies on MVID patient biopsies and the recent analysis of the Myo5b knockout mouse have indicated that certain transporter proteins, such as CD36, Na + /K + ATPase and transferrin receptor, are mislocalised in the absence of Myosin Vb function, indicative of a partial disruption of apico-basal polarity in mature enterocytes (Ameen and Salas, 2000, Carton-Garcia et al, 2015, Muller et al, 2008, Thoeni et al, 2014). We asked whether cell polarity is disrupted along with cell shapes in the enterocytes of gsp mutant larvae.…”

Section: Resultsmentioning

confidence: 99%

“…Analysis of intestinal cells of MVID patients has shown the presence of large vesicular structures called inclusion bodies with microvillar components trapped within (Ameen and Salas, 2000, Reinshagen et al, 2002, Thoeni et al, 2014, van der Velde et al, 2013). Enterocytes in Rab8a, Myo5b knockout mice and Myo5b deficient Caco2 cells exhibit the presence of actin rings marked by phalloidin, a classic feature of MVID (Carton-Garcia et al, 2015, Ruemmele et al, 2010, Sato et al, 2007, Schneeberger et al, 2015, Weis et al, 2016). To check if such inclusion bodies are present in the enterocytes of gsp/myoVb mutant larvae, intestines of 6dpf larvae were stained with phalloidin.…”

Section: Resultsmentioning

confidence: 99%

“…So far, the knockdown of myosin Vb using si-RNA in the Caco2 cell line has been used as a model for MVID (Ruemmele et al, 2010, Thoeni et al, 2014). Very recently, Myo5b knockout mouse models exhibiting attributes of MVID have been published (Carton-Garcia et al, 2015, Schneeberger et al, 2015, Weis et al, 2016). Other animal models for this disease include Rab8, Rab11a and Cdc42 knockout mice, which also exhibit microvillus inclusions in the enterocytes (Sakamori et al, 2012, Sato et al, 2007, Sobajima et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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The zebrafish goosepimples/myosin Vb mutant exhibits cellular attributes of human microvillus inclusion disease

Sidhaye

Pinto

Dharap

et al. 2016

Mechanisms of Development

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Microvillus inclusion disease (MVID) is a life-threatening enteropathy characterised by malabsorption and incapacitating fluid loss due to chronic diarrhoea. Histological analysis has revealed that enterocytes in MVID patients exhibit reduction of microvilli, presence of microvillus inclusion bodies and intestinal villus atrophy, whereas genetic linkage analysis has identified mutations in myosin Vb gene as the main cause of MVID. In order to understand the cellular basis of MVID and the associated formation of inclusion bodies, an animal model that develops ex utero and is tractable genetically as well as by microscopy would be highly useful. Here we report that the intestine of the zebrafish goosepimples (gsp)/myosin Vb (myoVb) mutant shows severe reduction in intestinal folds - structures similar to mammalian villi. The loss of folds is further correlated with changes in the shape of enterocytes. In striking similarity with MVID patients, zebrafish gsp/myoVb mutant larvae exhibit microvillus atrophy, microvillus inclusions and accumulation of secretory material in enterocytes. We propose that the zebrafish gsp/myoVb mutant is a valuable model to study the pathophysiology of MVID. Furthermore, owing to the advantages of zebrafish in screening libraries of small molecules, the gsp mutant will be an ideal tool to identify compounds having therapeutic value against MVID.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The zebrafish goosepimples/myosin Vb mutant exhibits cellular attributes of human microvillus inclusion disease

Sidhaye

Pinto

Dharap

et al. 2016

Mechanisms of Development

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“…During the review and revision process, the following paper was published, reporting another Myo5b mouse model for MVID (31).…”

Section: Methodsmentioning

confidence: 99%

An inducible mouse model for microvillus inclusion disease reveals a role for myosin Vb in apical and basolateral trafficking

Schneeberger

Vogel

Teunissen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Microvillus inclusion disease (MVID) is a rare intestinal enteropathy with an onset within a few days to months after birth, resulting in persistent watery diarrhea. Mutations in the myosin Vb gene (MYO5B) have been identified in the majority of MVID patients. However, the exact pathophysiology of MVID still remains unclear. To address the specific role of MYO5B in the intestine, we generated an intestine-specific conditional Myo5b-deficient (Myo5b ;Vil-CreERT2 intestines. In addition, we determined that MYO5B is involved not only in apical but also basolateral trafficking of proteins. The analysis of the intestine during the early onset of the disease revealed that subapical accumulation of secretory granules precedes occurrence of microvillus inclusions, indicating involvement of MYO5B in early differentiation of epithelial cells. By comparing our data with a novel MVID patient, we conclude that our mouse model completely recapitulates the intestinal phenotype of human MVID. This includes severe diarrhea, loss of microvilli, occurrence of microvillus inclusions, and subapical secretory granules. Thus, loss of MYO5B disturbs both apical and basolateral trafficking of proteins and causes MVID in mice.is a rare intestinal enteropathy with autosomal recessive inheritance, which was first described in 1978 (1). MVID patients cannot take up any nutrients and are often completely dependent on parenteral nutrition. The disease is characterized by villus atrophy, (partial) loss of microvilli on the apical plasma membrane of intestinal epithelial cells, and accumulation of intracellular vesicles/vacuoles, containing apical proteins and microvilli (2, 3). In addition, some studies also show mislocalization of apical and basolateral proteins, occasional crypt hyperplasia, and villus fusion (4-6).In the great majority of patients, MVID is caused by mutations in MYO5B, encoding the motorprotein, myosin Vb (5). In two patients, mutations in syntaxin 3 (STX3) caused a variant form of MVID (7). More than 41 unique mutations along the different regions in MYO5B have been identified in MVID patients, including deletions and nonsense, missense, and splice-site mutations (8-10). MYO5B is coding for the actin-based myosin 5b motor protein, which regulates apical membrane trafficking (5, 11). MYO5B functions as a homodimer and has three functional domains: an N-terminal motor domain, a calmodulin-binding domain, and a C-terminal tail, which binds cargo through association with the small GTPases RAB8A and/or RAB11A (12, 13). Altered expression of myosin Vb affects the apical membrane trafficking mechanism in epithelial cells, causing mislocalization of apical brush border proteins, such as villin (vil), CD10, or alkaline phosphatase (ALP) in the cytoplasm of duodenal enterocytes (2, 3, 5), and an increased apical localization of transferrin receptor (5,14).Although mouse models mimicking certain features of MVID have previously been described, such as Rab8 (15), Cdc42 (16, 17), and Rab11a knockout (KO) mice (18,19), no mutations in t...

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“…Rab11a knockout mice die in the postnatal period as a consequence of starvation. IEC of intestine-specific Rab8 or Myo5b-knockout mice, and individuals with microvillus inclusion disease that carry MYO5B mutations show very similar intracellular accumulation of resident apical plasma membrane proteins, microvillus atrophy, and microvillus inclusion bodies, yet died of diarrhea (Cutz et al 1989;Ameen and Salas 2000;Sato et al 2007;Cartó n-García et al 2015;Schneeberger et al 2015;Weis et al 2016). The apical transport abnormalities in IEC in Rab8-deficient mice may be the result of effects of Rab8a depletion on the secretion of Wnt ligands, which play an important role in intestinal epithelial morphogenesis (Das et al 2015).…”

Section: The Apical Recycling Endosomementioning

confidence: 99%

Mechanisms of Cell Polarity–Controlled Epithelial Homeostasis and Immunity in the Intestine

Klunder

Faber

Dijkstra

et al. 2017

Cold Spring Harb Perspect Biol

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Intestinal epithelial cell polarity is instrumental to maintain epithelial homeostasis and balance communications between the gut lumen and bodily tissue, thereby controlling the defense against gastrointestinal pathogens and maintenance of immune tolerance to commensal bacteria. In this review, we highlight recent advances with regard to the molecular mechanisms of cell polarity-controlled epithelial homeostasis and immunity in the human intestine.

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Myo5b knockout mice as a model of microvillus inclusion disease

Cited by 54 publications

References 27 publications

The zebrafish goosepimples/myosin Vb mutant exhibits cellular attributes of human microvillus inclusion disease

The zebrafish goosepimples/myosin Vb mutant exhibits cellular attributes of human microvillus inclusion disease

An inducible mouse model for microvillus inclusion disease reveals a role for myosin Vb in apical and basolateral trafficking

Mechanisms of Cell Polarity–Controlled Epithelial Homeostasis and Immunity in the Intestine

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