Research Projects

Human brain development is a highly orchestrated process which involves an array of cellular and molecular mechanisms over a long period of time. Perturbations in these processes lead to neurodevelopmental and neurological diseases. Neurodevelopmental disorders (NDDs) are a broad spectrum of diseases caused by defects neurodevelopmental processes at embryonic, neonatal and early childhood period and approximately 3% of children affected worldwide, comprising serious health problems. The etiologies of NDDs are largely unknown and often untreatable. Mutations (Homozygous or heterozygous or compound heterozygous) in several genes are associated with NDDs. Of these, homozygous and compound heterozygous mutations in DHX37 are associated with neurodevelopmental disease namely NEDBAVC (Neurodevelopmental Disorder with Brain Anomalies and with or without vertebral or cardiac anomalies, OMIM#618731). The symptoms of the children carrying mutations in DHX37 include severe microcephaly, seizures, cortical atrophy, polymicrogyria, dysgenesis of corpus callosum and overall developmental delay. However, the cellular and molecular functions of DHX37 in brain and development and how mutations contributing to developmental defects are largely unknown. DHX37 is a member of DEAH (Asp-Glu-Ala-His) domain containing DEAD box protein subfamily of RNA binding proteins. The gene DHX37 localized to chromosome 12q and encodes 130kDa protein which functionally acts as RNA helicase. DHX37 comprises two RecA-like domains and a helicase-associated domain (HA2), followed by an oligonucleotide binding fold (OB) domain. DHX37 plays an important role in biogenesis of 18S rRNA. In addition, DHX37 physically interacts with mRNAs of glycine receptor subunits namely GlyR α1, α3, α4a which are important in glycinergic synaptic transmission and positively regulates their expression in zebra fish. The loss of Dhx37 is compensated by overexpression of these glycine receptors to rescue the behavioral and motor defects. However, the cellular functions of DHX37 in brain development are largely understudied. CRIPSR edited human iPSCs (induced Pluripotent Stem Cells) or ESCs (Embryonic Stem Cells) will be utilized to generate 2D cultures of neural stem cells (NSCs) to understand the role of DHX37 in their proliferation and differentiation. These NSCs (Endogenously FLAG-tagged DHX37) will be utilized to find interactome of DHX37 and uncover the cellular are molecular functions. Human cerebral brain organoids (derived from human iPSCs or ESCs) recapitulate developmental hallmarks of the human brain, including ventricular zone (VZ) which contain apical radial glia, subventricular zone (SVZ) with intermediate progenitors and outer radial glia, and an emerging cortical plate (CP) that contains neurons. Utilization of human brain organoids to model NEDBAVC will discover the novel functions of DHX37 in early brain development and unable to understand how mutations contributing to brain anomalies.