The Ups and Downs of miRNA and MeCP2 in Fetal Brains

What goes up must come down. And in the developing human brain, when miR-483-5p levels go up, it makes MeCP2 levels go down, according to researchers in a recent report.

Problems with MeCP2 cause Rett Syndrome and other neurological disorders. MeCP2 levels are low in fetal stages of development, but high after birth in the human brain. But how that all happens remained a mystery.

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Because the MeCP2 transcript can have different 3’ UTR lengths—and the repressed MeCP2 was correlated with the long 3’ UTR—the team from Texas, Connecticut, California, and Canada thought maybe miRNAs binding to the long 3’UTR had something to do with it.

Using “coexpression meta-analysis of miRNA targets” (CoMeTa) and other strategies, the team found that miR-483-5p was probably the elusive MeCP2 regulator. Here’s a little more of what they discovered:

  • The miR-483-5p regulates MeCP2 via a human-specific binding site.
  • miR-483-5p is located within the imprinted gene IGF2.
  • When miR-483-5p is overexpressed in cells, MeCP2 is reduced.
  • There’s a lot of miR-483-5p in human fetal brains, but low amounts of MeCP2.
  • Expressing miR-483-5p in hippocampal neurons fixes them from defects due to too much MeCP2.
  • miR-483-5p also appears to regulate levels of other proteins that interact with MeCP2 in complexes.

“The discovery that miR-483-5p regulates MeCP2 levels surprised me in two ways,” says Huda Zoghbi, the leader of the study, who is a Howard Hughes Medical Institute investigator and professor at Baylor College of Medicine. “The first being that the binding site of miR-483-5p to MECP2 is specific to humans, and the second is that the microRNA regulates levels of two proteins that interact with MeCP2. The odds are that this regulatory mechanism involves many other genes that function together and/or that express 3’UTRs in a developmental or tissue specific pattern.”

Get all the details at Genes & Development, February 2013.