The Sun Lab studies the most numerous cells in the brain, called “glia”. Glia are essential for brain development, and glial abnormalities are associated with many neurological diseases, including cerebral palsy, stroke, autism, traumatic injury, multiple sclerosis (MS), and Alzheimer’s disease (AD). Dysregulation of glia often occurs prior to the onset of many neurological diseases, suggesting that they may drive disease occurrence and progression. However, the mechanisms underlying glial development and their communication with other cells remain poorly understood. We are dedicated to addressing the fundamental principles that govern glial formation and their communication with other cells in both health and disease.
In vertebrates (including humans), nearly half of the brain cells are non-neuronal cells. Most of them are glia, including oligodendrocytes, astrocytes, and microglia. Unlike neurons, glial cells do not fire action potentials, but they are essential for normal nervous system function. We have focused on oligodendrocytes, the sole myelin-producing cells in the central nervous system. Individual oligodendrocytes extend 3-80 processes (known as internodes) to myelinate nearby axons, thereby forming the myelin sheaths and providing critical insulation, trophic support, and antioxidant defense for axons. Because of their abundance, nearly half of the human brain’s dry mass is composed of oligodendrocytes and myelin. Despite their importance, how oligodendrocytes develop, myelinate axons, and become dysfunctional in diseases remains poorly understood.
Our lab is dedicated to addressing these questions with multidisciplinary approaches. We have combined mouse genetics, oligodendrocyte-neuron co-culture, volume electron microscopy, functional multiomics, and neurophysiology to investigate the underlying cellular and molecular mechanisms. Understanding how oligodendrocytes develop and communicate with other cells is essential to tackle many neurological diseases, including cerebral palsy, demyelinating diseases, glioblastoma, and dementia, that are significantly affected by oligodendrocyte and myelin dysfunction.
We are seeking highly motivated postdoctoral fellows and graduate students to join our team.
Our Research
Genetic decoding of the bottleneck in oligodendrogenesis
During both development and myelin repair, oligodendrocyte progenitor cells (OPCs) must exit the cell cycle and differentiate into premyelinating oligodendrocytes (preOLs) before myelinating axons. Despite being transient, preOLs are at a critical stage of myelination, known as axon ensheathment. At this stage, they extend several processes to survey and begin ensheathing nearby axons. Due to their critical roles in oligodendrogenesis, dysregulation of preOL survival and maturation is evident in multiple sclerosis and perinatal white matter injury. The lack of genetic tools to visualize and manipulate preOLs has left this critical differentiation stage woefully understudied. Using the Easi-CRISPR, we have engineered a CreERT2 knock-in mouse line that allows genetic labeling, lineage tracing, manipulation, and multimodal profiling of preOL subsets across the central nervous system (Bhambri et al., 2024 BioRxiv; Nature Neuroscience, accepted). Our work provides a new tool to probe this critical cell stage during development, allowing for the investigation of myelin establishment.
Genome-wide CRISPR knockout screens to identify new players in oligodendrogenesis
To uncover the intrinsic mechanisms governing CNS myelination, we have developed a primary oligodendrocyte-based, genome-wide CRISPR knockout screen platform that enables us to identify several new pathways controlling oligodendrogenesis. Specifically, we established a new method to purify primary murine oligodendrocyte precursor cells and expand them in large quantities sufficient for genome-wide CRISPR screens. Our method ensures that these proliferating oligodendrocyte progenitor cells maintain essential properties of their in vivo counterparts and display stereotypical differentiation in culture. Using this system, we have identified several pathways that have been poorly studied in myelination. We are developing an in vivo CRISPR screen to fully understand the intrinsic and extrinsic mechanisms underlying myelination.
The communications between neurons and glial cells, as well as the ones among different glial cell types (astrocytes, oligodendrocytes, and microglia) are critical for normal nervous system function. The molecular and cellular mechanisms underlying these communications remain largely unknown. Oligodendrocyte-axon unit provides an excellent model to study neuron-glia interactions. Specifically, we are interested in the mechanisms that establish the initial axonal ensheathment by oligodendrocyte processes. Recent work showed that, intriguingly, the nervous system is inadequately myelinated; only a small portion of axons are myelinated even in the adulthood. In addition, there are also many unmyelinated segments along the myelinated axons. How do oligodendrocytes choose subsets of axons to myelinate? Is there any selectivity between axons and individual oligodendrocyte’s processes (20-30 per oligodendrocyte) that will myelinate these axons? What are the mechanisms governing the regional and temporal specificity across diverse brain regions? To address these questions, we have established primary oligodendrocyte-neuron co-culture platform as well as multiple in vivo murine systems, including the optic nerve (fully myelinated), the cortex (partially myelinated), and the cerebellum molecular layer (no myelination).
Gliosis was observed hundreds of years ago. It is tightly associated with many neurological diseases, including stroke, traumatic injury, multiple sclerosis (MS), Alzheimer’s Disease (AD), and Amyotrophic Lateral Sclerosis (ALS). In recent years, glial abnormality has been shown to occur before the onset of many neurological diseases, suggesting that glial cells may drive disease progression. Therefore, probing glial cells provides a unique angle in understanding and possibly treating these diseases. We are devoted to understanding the mechanisms underlying oligodendrocyte-associated diseases, including demyelinating diseases like neonatal white matter injury and multiple sclerosis. We have identified a few molecular handles and have established several animal models to address demyelination and remyelination mechanisms. In addition, we are interested in non-canonical oligodendrocyte diseases, including psychiatric disease and AD in which oligodendrocyte-specific genes are mysteriously dysregulated.
