Indian researchers turn to zebrafish to study microvillus inclusion disease

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The intestinal defects in zebrafish are identical to humans. – Photo: Mahendra Sonawana

Indian researchers have finally found an ideal animal model to study microvillus inclusion disease (MVID) that may affect children born out of consanguineous marriages and to screen potential drugs to treat the disease. Currently, children with MVID disease have no treatment and mostly die premature as babies as they suffer from malabsorption of nutrients and huge fluid loss due to chronic diarrhoea.

Working with zebrafish a few years ago, Dr. Mahendra Sonawane from Mumbai’s Tata Institute of Fundamental Research (TIFR) and his team showed that mutations in myosin Vb gene lead to defects in epidermis development. But the epidermis defect gets partially resolved and the mutant fishes start growing normally before eventually dying 12-15 days after birth. “We did not know why these mutant fishes were dying. We suspected that there must be a defect in the intestine,” says Dr. Sonawane.

In humans, mutations in the myosin Vb gene have been linked to microvillus inclusion disease. This gene encodes for a protein that acts as a motor to transport small vesicles that carry proteins and secretary material from the inner part of the cell to the cell membrane or outside the cells.

Aside from the link to MVID, the gene is expressed in the intestinal epithelium of zebrafish.  So Dr. Sonawane’s team started looking for the morphology of the intestine when the myosin Vb function is lost due to mutations. The results of the study were published recently in the journal Mechanisms of Development.

The scientists expected zebrafish with the myosin Vb mutation to exhibit some defects. “We were surprised to find that the intestinal defects in zebrafish were almost identical to humans,” he recalls. For instance, the microvilli, which are essential for absorption of nutrients, were stunted in most cases and even completely absent in extreme cases.

The intestinal folds increase the surface area of the inner intestinal wall.  But the folds were found lacking in fishes that had the myosin Vb mutation; the walls appeared smooth instead. And this is presumably due to changes in the intestinal cell shape and density.

zebrafish embryos
Zebrafish makes it easy to examine the defects in the intestine as embryos are transparent.

The third main feature that causes malabsorption of nutrients is the presence of large vesicular bodies in the intestinal cells called inclusion bodies. The inclusion bodies were found to trap microvilli inside them thereby preventing the microvilli from being exposed on the surface of the intestinal wall.

Though normal and mutant larvae ingested chicken egg yolk, the ability of mutant larvae to absorb lipids was less compared with normal fish, thus testifying the decreased capacity of intestinal cells to absorb nutrients.

The zebrafish disease model has two major advantages over mice disease models for MVID.  First, it is easy to examine the defects in the intestine as embryos and early larvae develop outside the mother and are transparent.  Second, each zebrafish couple produces 100-250 embryos and, hence, enough mutant embryos (quarter of the total progeny) can be obtained for analyses.

Dr. Niranjan Thomas, a specialist in neonatology from Christian Medical College Vellore, who reported an MVID case in India, thinks that the disease probably goes under-diagnosed in India. “This disease is prevalent in Turkish population due to consanguineous marriages. Since such marriages are not uncommon in India, it is surprising that only two cases of MVID have been reported so far,” Dr. Sonawane says. “There is a need to track familial history in Indian population followed by genetic screening for MVID especially when couples lose babies due to chronic diarrhoea soon after birth.”

Published in The Hindu on September 11, 2016

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