Microcephaly is a neurodevelopmental condition leading to an underdeveloped brain that adversely affects learning and behaviour.

About 1 in 2,000 babies in Australia are reported to have microcephaly. There currently is no known cure or standard treatment for the disorder.

Neurons are the fundamental building blocks of the nervous system, responsible for transmitting electrical and chemical signals that enable communication between different parts of the body and the brain.

The new WEHI-led study is the first to show that Trabid plays a critical role in the development of healthy neurons by ensuring they are guided correctly in the developing brain – ultimately enabling normal brain function and behaviour.

Co-lead author, Associate Professor Grant Dewson, said the findings may aid diagnosis and treatment of neurodevelopmental disorders in the future, with 2.5 million Australians believed to be living with one of these conditions.

“Our understanding into how neurodevelopmental conditions, like microcephaly, develop continues to grow,” Assoc Prof Dewson, a Laboratory Head at WEHI, said.

“While previous research has indicated there could be a link between defects in Trabid and microcephaly, our study is the first to provide evidence for the gene’s function in neuronal guidance –filling a vital knowledge gap.”

The study, with first authors Dr Daniel Frank, Dr Maria Bergamasco (now at Charles Perkins institute, University of Sydney), Dr Michael Mlodzianoski, is published in the journal, eLife.

In 2015, UK researchers published a study that first suggested a possible connection between the gene encoding Trabid (ZRANB1) and microcephaly, after identifying two patients with the brain disorder who had mutations in this gene.

Dr Hoanh Tran, who has over 10 years of experience investigating Trabid, was able to build on this research by characterising these patient mutations in the lab using pre-clinical models.

“Abnormalities in neuron migration and guidance can lead to neurodevelopmental disorders like microcephaly” Dr Tran said.

“Cells in the developing brain must migrate to the right location. If the address is missed, developmental defects can occur.

“Healthy neurons extend long processes called axons in a directional, ordered manner. In our study, we found the neurons from models with defective Trabid project axons that migrate with a wayward trajectory.

“These significant findings provide an understanding of Trabid/ZRANB1 as a new human microcephaly gene.”

Currently, microcephaly can sometimes be diagnosed with an ultrasound test during the second or third trimester.

The team hopes that, in future, defects in Trabid, or the proteins that Trabid controls, could help identify babies who are at-risk of developing microcephaly – allowing for potential early interventions.

The research involved collaborations between WEHI’s Ubiquitin Signalling Division, Epigenetics and Development Division, Centre for Dynamic Imaging and Professor Elizabeth Vincan and her team from The Peter Doherty Institute for Infection and Immunity.

The work was supported by the National Health and Medical Research Council, the Bodhi Education Fund, Phenomics Australia, the Australian Government and the Victorian State Government.

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Header image: This image shows neurons and their connections to each other in red and yellow, and the cell’s DNA in blue. WEHI researchers have, for the first time, uncovered the Trabid protein’s critical role in the development of healthy neurons, which are essential for the proper functioning of our nervous system and overall quality of life.  Credit: Simone Seizova and Shiraz Tyebji, WEHI