A team of Mizzou biologists, led by Dr. Yves Chabu, has made a new discovery that provides molecular clues into what happens in developing brains that may cause microcephaly. 

Microcephaly is a rare condition where a baby is born with an abnormally small head. Previous studies have found that individuals with mutations in a gene called JNK-Interacting Protein 3 (JIP3) show brain development defects, including microcephaly. The nature of the association, however, is not well understood.

In a study looking at wing size development in flies, Chabu and colleagues report that JIP3 is required for proper wing size and that suppressing its expression results in smaller adult wings. Through a series of experiments, they show that JIP3 functions in the Hippo signaling pathway, which is known as a central organ size regulator across species, including humans. JIP3 sits between two proteins, Yorkie and the cell death inhibitor Diap1, that work in concert to drive cell proliferation while blocking cell death, hence promoting tissue growth. They show that JIP3 regulates wing size by controlling the stability of Diap1, acting as a sort of “tuning mechanism” for scaling organ size. In further experiments, they show that JIP3 similarly regulates Yorkie-mediated cell growth in mammalian cells. 

“The study provides important mechanistic insight into our basic understanding of the molecular underpinnings of organ size regulation as well as the recent and perplexing association between JIP3 mutations and microcephaly in human patients,” said Chabu.

The authors report their findings in the journal Developmental Biology.  

Drs. Vakil Ahmad and Gangadhar Vadla, postdoctoral fellows in the Chabu lab, helped design the research, performed the experiments and analyzed the data. Dr. Ahmad is lead author of the study.