Title: Investigation of the epitranscriptomic mechanisms of microcephaly using human brain organoids.
Funder: The Academy of Medical Sciences

Abstract: In this proposal, we seek to investigate the cellular and molecular mechanisms of autosomal recessive primary microcephaly, a disorder characterized by reduced brain size and life-long complications such as intellectual disability. The goal of this proposal is to investigate the novel epitranscriptomic role of the microcephaly gene, METTL5 in translational control of gene expression during human cortical development. METTL5 is a methyltransferase that catalyses N6-methyladenosine (m6A) modification in 18S ribosomal RNA (rRNA). On 18S rRNA, m6A plays a critical role in fine-tuning translation by contributing to mRNA-specific translational efficiency and ribosome heterogeneity. We hypothesize that METTL5-mediated ribosomal heterogeneity regulates the translation of a subset of genes that are critical for neural stem cell behaviours during neocortical development. To test this novel hypothesis, we will use forebrain organoids from human induced pluripotent stem cells, which recapitulate essential features of the developing human cortex including cell heterogeneity, cellular organization, and transcriptomic signatures of different stages of brain development. This proposal is based on my expertise on brain development, brain organoid culture, and m6A RNA modification, which were developed by my previous works; i) investigation of neurodevelopmental disorder risk genes during cortical development using human forebrain organoids, and ii) examination of the role of m6A modification on the epitranscriptomic regulation of the key genes for the survival of Purkinje neurons in the cerebellum. This study will lead to a key mechanistic understanding of human cortical development as well as novel insights into the therapeutics and interventions of microcephaly.

Lay abstract: Microcephaly is a neurodevelopmental disorder characterized by reduced brain size. Babies born with microcephaly may develop convulsions and suffer physical and learning disabilities as they grow older. While the clinical aspects of microcephaly are well characterized, the cellular and molecular mechanisms are not well understood, limiting possible interventions and therapeutics of the disorder. The overarching goal of this proposal is to uncover the cellular and molecular mechanisms behind microcephaly by investigating the function of a microcephaly causing gene in neural stem cells during brain development using human brain organoids. Human brain organoids are 3D self-assembled structures of brain cells, which recapitulate the cellular organization and structure of the developing human brain. Brain organoids provide unique opportunities to model human brain developmental and pathological processes not otherwise available with alternative approaches. Through this study, we will gain a better understanding of the mechanisms underpinning human brain development and the underlying cause of microcephaly at the molecular and cellular level, which will lead to novel insight into the therapeutics and interventions of the disorder.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL