Study identifies novel mechanism that causes abnormal brain development.
Autism Spectrum Disorders (ASDs) are a group of highly inheritable behavioural disorders that pose major personal and public health concerns. Patients with ASDs have mild to severe communication difficulties, repetitive behaviour and social challenges. Such disorders significantly challenge an individual’s ability to conduct daily activities and function normally in society. Currently there are very few medication options that effectively treat ASDs.
Recognising a need to better understand the biology that produces ASD symptoms, scientists at Duke-NUS Medical School (Duke-NUS) and the National Neuroscience Institute (NNI), Singapore, have teamed up and identified a novel mechanism that potentially links abnormal brain development to the cause of ASDs. This new knowledge will help to improve the diagnosis and development of therapeutic interventions for ASDs.
In the study, published today in the journal eLife, co-senior authors Assistant Professor Shawn Je from Duke-NUS and Assistant Professor Zeng Li from NNI have shown how one brain-specific microRNA (miR-128) plays a key role in causing abnormal brain development. MicroRNAs are small molecules that regulate gene expression in the human body to ensure proper cellular functions. Although it was known that miR-128 is misregulated in some patients with autism, what that meant and how it functioned was not known.
The Duke-NUS and NNI team showed that miR-128 targets a protein called PCM1 that is critical to the cell division of neural precursor cells (NPCs). NPCs during early brain development have two fates – they either stay as NPCs and undergo self-renewal or become neurons through differentiation. The dysfunctional regulation of PCM1 by misregulated miR-128 impairs brain development, which may underlie brain size changes in people with ASDs.
“For the first time, we have managed to show that miR-128 is a mechanism that regulates early neuronal behaviour during brain development,” said Asst Prof Je, from the Neuroscience and Behavioural Disorders (NBD) Programme at Duke-NUS. “Targeting this mechanism may be the answer to diagnose and treat ASDs that are caused by abnormal brain development.”
Asst Prof Li, from the Neural Stem Cells Laboratory at NNI, added, “This important study suggests a link between a key neurological disease gene and regulation of microRNAs in the brain. However, we are just starting to understand how misregulated miR-128 expression can cause our brain activities to go wrong, and much more work needs to be done.”
In a separate study which is not yet published, this team with Professor Steve Rozen, from the NBD Programme at Duke-NUS, identified many new mutations in the PCM1 gene from ASD patients from next-generation sequencing. Future work to correlate these mutations with functional consequences in brain development should not only increase the understanding of how autism is caused, but also enable a more accurate diagnosis of autism and other ASDs.
About this neurology research
Study authors include first authors, Dr Zhang Wei, a Post-Doctoral Fellow from the NNI and MD/PhD student Paul Kim from Duke-NUS.
Funding: Research is supported by the A*STAR Translational Clinical Research Partnership Award.
Source: Dharshini Subbiah – Duke NUS Medical School Image Source: The image is in the public domain. Original Research: Full open access research for “MiRNA-128 regulates the proliferation and neurogenesis of neural precursors by targeting PCM1 in the developing cortex” by Wei Zhang, Paul Jong Kim, Zhongcan Chen, Hidayat Lokman, Lifeng Qiu, Ke Zhang, Steven George Rozen, Eng King Tan, Hyunsoo Shawn Je, and Li Zeng in eLife. Published online February 17 2016 doi:10.7554/eLife.11324
MiRNA-128 regulates the proliferation and neurogenesis of neural precursors by targeting PCM1 in the developing cortex
During the development, tight regulation of the expansion of neural progenitor cells (NPCs) and their differentiation into neurons is crucial for normal cortical formation and function. In this study, we demonstrate that microRNA (miR)-128 regulates the proliferation and differentiation of NPCs by repressing pericentriolar material 1 (PCM1). Specifically, overexpression of miR-128 reduced NPC proliferation but promoted NPC differentiation into neurons both in vivo and in vitro. In contrast, the reduction of endogenous miR-128 elicited the opposite effects. Overexpression of miR-128 suppressed the translation of PCM1, and knockdown of endogenous PCM1 phenocopied the observed effects of miR-128 overexpression. Furthermore, concomitant overexpression of PCM1 and miR-128 in NPCs rescued the phenotype associated with miR-128 overexpression, enhancing neurogenesis but inhibiting proliferation, both in vitro and in utero. Taken together, these results demonstrate a novel mechanism by which miR-128 regulates the proliferation and differentiation of NPCs in the developing neocortex.
“MiRNA-128 regulates the proliferation and neurogenesis of neural precursors by targeting PCM1 in the developing cortex” by Wei Zhang, Paul Jong Kim, Zhongcan Chen, Hidayat Lokman, Lifeng Qiu, Ke Zhang, Steven George Rozen, Eng King Tan, Hyunsoo Shawn Je, and Li Zeng in eLife. Published online February 17 2016 doi:10.7554/eLife.11324