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Linking fragile X to unregulated tissue growth
An inheritable genetic condition, fragile X syndrome is estimated to cause mild to moderate intellectual disabilities in 1 in 4,000 to 5,000 males and 1 in 6,000 to 8,000 females. It also causes physical abnormalities such as large brain size and weight at birth, unusually fast growth in height, gastrointestinal issues and a high risk for obesity.
A study conducted in fruit flies focused on the effects of losing the same protein, RNA-binding fragile X mental retardation protein (FMRP), that is found in the intestines of the fly and missing in people with fragile X syndrome. The work is reported in Cell Reports.
"To our knowledge, this is the first study to find a stem cell based mechanism by which a protein that is absent in people with fragile X syndrome, limits excessive organ growth. This could represent a root cause for the gastrointestinal problems seen in people with the condition."
Similarly, Luhur holds that the stem-cell-based mechanism could cause symptoms seen in other parts of the body in fragile X syndrome, such as accelerated height due to unrestrained bone stem cell growth, or mental problems caused by excess neurons.
Fragile X syndrome is caused by an error in a single gene in the X chromosome called FMR1. Typically, the FMR1 gene creates a protein called FMRP. In individuals with fragile X syndrome, an abnormality in this gene causes the body to "silence" the production of FMRP.
The IU team found that the absence of FMRP causes a higher frequency of cellular duplication - driven by symmetric stem cell division. Typically, this process is balanced by asymmetric stem cell division, when old cells are replaced with new ones.
"The cells that lacked FMRP acted like cars without brakes. They were ready to divide more often and more quickly, tending to divide symmetrically, causing the intestine to be bigger than normal."
The discovery grew from researchers' earlier work on another gene, LIN-28, that also appeared to affect growth in the intestinal cells of fruit flies. In that study, IU researchers saw that FMRP - the protein encoded by the gene that causes fragile X syndrome - played a role in the same biomolecular pathway as LIN-28.
In that study, lower levels of LIN-28 reduced insulin receptors in fruit fly intestines, slowing cellular duplication and tissue growth. The new study finds that stem cells from intestines of flies with the genetic mutation for fragile X activated these insulin receptors at a higher rate than in normal cells. Moreover, higher levels of FMRP affected LIN-28 levels, but not vice versa. This suggests FMRP plays a controlling role in that biological pathway.
Luhur notes that basic biological research into fragile X syndrome's non-neurological symptoms is equally important as these effects are understudied and undertreated when compared to problems in mental development.
Luhur believes the current work may open doors to new treatments for fragile X syndrome as they found normal cell growth could be restored by reducing the insulin-signaling activity in fruit flies' intestines through genetic interventions as well as through changes in nutrition.
The connection between insulin receptor activity and intestinal growth may stimulate more research, as the FDA-approved diabetes drug Metformin seems to alleviate some neurological symptoms of fragile X syndrome.
Luhur: "The next step is conducting additional research on FMR1 and LIN-28 in animals to learn more about their biochemical relationship and their effect on metabolism in the body. These are important questions for understanding how their interaction affects physiology and human health."
• FMRP limits adaptive tissue expansion in the adult Drosophila intestine
• FMRP represses symmetric division and insulin sensitivity of intestinal stem cells
• FMRP mediates its effect in intestinal stem cells solely via LIN-28
• The study of African skin color identifies novel and canonical pigmentation genes.
Although the intrinsic mechanisms that control whether stem cells divide symmetrically or asymmetrically underlie tissue growth and homeostasis, they remain poorly defined. We report that the RNA-binding protein fragile X mental retardation protein (FMRP) limits the symmetric division, and resulting expansion, of the stem cell population during adaptive intestinal growth in Drosophila. The elevated insulin sensitivity that FMRP-deficient progenitor cells display contributes to their accelerated expansion, which is suppressed by the depletion of insulin-signaling components. This FMRP activity is mediated solely via a second conserved RNA-binding protein, LIN-28, known to boost insulin signaling in stem cells. Via LIN-28, FMRP controls progenitor cell behavior by post-transcriptionally repressing the level of insulin receptor (InR). This study identifies the stem cell-based mechanism by which FMRP controls tissue adaptation, and it raises the possibility that defective adaptive growth underlies the accelerated growth, gastrointestinal, and other symptoms that affect fragile X syndrome patients.
Authors: Arthur Luhur, Kasun Buddika, Ishara Surangi Ariyapala, Shengyao Chen, Nicholas Samuel Sokol
We thank Kendal Broadie, Stephen Cohen, Tom Jongens, Norbert Perrimon, the Bloomington Drosophila Stock Centers, the Developmental Studies Hybridoma Bank, and the Drosophila Genome Resource Center for reagents; the Indiana Statistical Consulting Center for math advice; Brian Calvi and Andrew Zelhof and two anonymous reviewers for comments that improved the manuscript; and the NIH (awards R21OD019916 and R01GM124220 ) and Indiana University for financial support.
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LIN-28 predominates during adaptive growth to promote the mRNA translation needed for symmetric ISC division and expansion. FMRP activates later, during transition from growth to homeostasis, in order to recruit LIN-28-repressive mRNPs and switch the ISC division pattern from symmetric to asymmetric. Image credit: the authors.