Dr. Jiami Guo

My lab aims to identify fundamental principles governing the construction of neural circuits in development and disease. We have been focused on the primary cilium, an essential sensor and conveyor of extracellular signals underlying major cell functions. Long considered as evolutionary remnants of little significance, primary cilia in the past two decades have sparked enormous interest, fueled by the discoveries that mutations in 200+ ciliary genes lead to 30+ human disorders collectively termed “ciliopathies”. The brain is particularly vulnerable to ciliary defects. Patients of ciliopathies show neurological and cognitive deficits and are often diagnosed with intellectual disability, autism spectrum disorders, schizophrenia, bipolar disorder, epilepsy, depression, and anxiety. Recent emerging evidence has also suggested a strong link between primary ciliary function and neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic lateral sclerosis (ALS). However, long-standing question remains: How do primary cilia, only a few mm long protrusions from the cell soma, exert such a profound impact in the brain? My research program is dedicated to solving this mystery. Our work made great strides in filling the gaps in our understanding of primary cilia’s function in neural and glial development and established an innovative experimental platform to interrogate ciliary signaling in the brain (Higginbotham and Guo et al., Nature Neuroscience 2013; Guo and Higginbotham et al., Nature Communications 2015; Guo et al., Developmental Cell 2017, 2019; Wang et al., Nature Neuroscience 2024). We are incorporating recent advances across a wide range of disciplines based in molecular genetics, biochemistry, cell biology, live imaging, neuroscience, and translational pharmacology to peel back the layers of this mystery from gene→cell→circuit→ behavior→therapeutics. By assembling a holistic view of how primary cilia convey environmental signals to impact brain development and function, these efforts will not only uncover an underappreciated cell biological mechanism fundamental for neural circuit construction and malformation but also advance our understanding of how genetic and environmental insults interact to contribute to the etiology of neurological disorders. 

There are more than 600 known diseases affecting the nervous system. Whether triggered by a pathogen, genetics, aging, or a physical impact, neuroinflammation—the immune response in the brain, plays a role in nearly all of them. Normally a guard against insults by promoting repair and healing, neuroinflammation can become a driver for pathology when chronic or excessive. This dichotomy is caused by the complex and dynamic nature of immune cells and their intricate cell-cell crosstalk. Astrocytes are the brain-resident immune cells and central players in this dichotomy by initiating and escalating neuroinflammation. Due to their different immune responses, astrocytes can exert either beneficial or detrimental effects on brain health and diseases. However, what drives their “protective” vs. “pathological” states remains poorly understood.

We focused on primary cilia, underappreciated signaling sensors in almost all astrocytes. Our work suggests that primary ciliary signaling modulates astrocyte immune reaction and their crosstalk with other cell types, which collectively change the neuroinflammation trajectory and tissue injury response. We aim to provide mechanistic insights into the cilia-driven modulation of neuroinflammation and take the next leap in developing primary cilia control methods for therapeutic strategies.