Molecular, Cellular, Developmental Neuroscience
The main goal of our research is to identify fundamental principles governing the construction of neural circuits in development and disease. Towards this goal, we are currently focused on the dynamic function of the primary cilium, a tiny signaling antenna of a cell. Primary cilia are present on almost all cell types and are essential for coordinating major cell functions in response to environmental signals. The critical role of primary cilia in brain development is evident in human disease states called ciliopathies, where defective cilia lead to brain malformations associated with neurodevelopmental disorders such as autism and intellectual disabilities. We use a combination of mouse genetics, innovative cilia-specific signaling modulation, and viral-genetic circuit mapping to delineate primary cilia in the emergence of neuronal morphology and connectivity, key steps in neural circuit formation. By assembling a holistic view of how primary cilia translate environmental signals to impact neural development, we aim not only to uncover hitherto undefined cell biological mechanisms fundamental for neural circuit construction and malformation, but also to advance our understanding of how genetics and environment interact to contribute to the etiology of neurodevelopmental disorders. The long-term goal of the Guo lab is to define fundamental principles governing the functional wiring of the brain. Towards this goal, we are focused on primary cilia, signaling antennae of almost all cells in the brain. Long considered as evolutionary remnants of little significance, primary cilia in the past decade have sparked enormous interest, fueled by the discoveries that mutations in 150+ ciliary genes lead to 30+ human disorders collectively termed “ciliopathies”. The brain is particularly vulnerable to ciliary dysfunction as reflected by the prominent brain anomalies and neurological deficits associated with neurodevelopmental and psychiatric disorders found in ciliopathy patients. Nevertheless, due to the lack of mechanistic insights, how primary cilia can exert such a profound impact on the brain remains a long-standing mystery. How do primary cilia, only a few um long protrusions from the cell soma, exert such a profound impact in the brain? The Guo lab is incorporating recent technical advances, including single-cell/nucleus RNAseq and ATACseq, human iPSCs, Serial Block face EM, mouse genetics, biochemistry, cell signaling control, in vivo 2-photon live imaging, and translational pharmacology to peel back the layers of this mystery from gene→cell→circuit→behavior→therapeutics (Guo et al., Developmental Cell 2017; Guo et al., Developmental Cell 2019; Wang et al., Nature Neuroscience 2024). The Guo lab has established a wide range of national and international collaborations. Postdoctoral fellows and PhD students in the Guo lab have ample opportunities to learn cutting-edge technologies in molecular/cellular/system neuroscience.