The X. Zhang lab studies fundamental mechanisms of brain development with the ultimate goal of diagnosing and treating neurological disorders. Our current research centers on:

Neurogenesis in the cerebral cortex: The six-layered neocortex is an evolutionary feature in mammals. While diverse neuronal cell types have been identified in the brain, molecular mechanisms underlying the developmental production and specification of neuron subtypes remain to be fully understood. Recent single-cell transcriptome analyses (Ruan and Kang et al., 2021) from the lab uncovered temporal gene expression in apical and basal progenitors. Whether such dynamic gene expression regulate neural progenitor cell behavior remains unclear. We are interested in understanding how neural progenitors change their proliferation and differentiation capacity as well as other stereotypical features over time using molecular, cellular, and genetic approaches. These studies will help to understand mechanisms of neurogenesis, neuronal migration (Zhang et al., 2009), and cell type specification in the neocortex.

mRNA isoforms and neural development: Alternative mRNA processing generates remarkable molecular diversity and in extreme cases enables a single gene to produce hundreds of isoforms. What are the functions and mechanisms of alternative mRNA splicing and polyadenylation in the brain? Single-cell and genetic analyses from us and others start to uncover cell type-specific mRNA isoforms in developing human and mouse brains (Zhang et al., 2016) and human iPSC-derived cerebral organoids (Yang and Yang et al., 2023). We take advantage of single-cell and spatial transcriptomic data, and investigate cell type-specific polyadenylation in the brain (Kang et al., 2023). These analyses enrich the annotation of mRNA forms, profile their dynamic expression during brain development, and facilitate the functional annotation of human mutations. We are studying functions of mRNA isoforms in neural development using genetic approaches and developing RNA deaminase-based recording methods to investigate the mechanisms of protein-RNA interaction (Ruan et al., 2023).

Neurodevelopmental disorders — genetic discovery, pathogenic mechanism, and targeted therapy. DNA mutations that affect brain development can cause congenital diseases such as autism and epilepsy. We are interested in understanding the causal variants and pathogenic mechanisms of neurodevelopmental disorders (Qi et al., 2022; Zhang et al., 2014). We are particularly interested in the roles of alternative mRNA isoforms in neuronal gene regulation and disease pathogenesis. Taking advantage of the accumulating wealth of transcriptomic methods and resources, we have started to use molecular, genetic, and developmental biology approaches to study the functions and regulatory mechanisms of mRNA isoforms in the brain. Redirecting splicing has been recognized as a promising approach to treat neurological disorders, and our study will generate insights and reagents toward the ultimate goal of precision medicine. As an example, our recent work indicates that redirecting alternative splicing alleviates SYNGAP1 haploinsufficiency in models of human diseases (Yang and Feng et al., 2023).

At the University of Chicago, we work closely with labs within the Department of Human Genetics which has unusual strength in genetics, genomics, and computational biology. We share strong interest and collaborate with colleagues in neuroscience, statistics, developmental biology, systems and RNA biology, and pediatrics. Through collaborative efforts, our group seeks to understand fundamental mechanisms of brain development and gene regulation.