VERTEBRATE NEURAL DEVELOPMENT
We use zebrafish as a model system to investigate mechanisms that guide formation
of the vertebrate nervous system. The rapid development, optical clarity, and small
size of zebrafish embryos and larvae allow us to directly observe cell behaviors in
living animals using confocal light microscopy. Combined with deep sequencing and
methods for genome modification, this enables detailed investigation of the genetic
and molecular mechanisms that guide neural cell specification, differentiation,
and function.
of the vertebrate nervous system. The rapid development, optical clarity, and small
size of zebrafish embryos and larvae allow us to directly observe cell behaviors in
living animals using confocal light microscopy. Combined with deep sequencing and
methods for genome modification, this enables detailed investigation of the genetic
and molecular mechanisms that guide neural cell specification, differentiation,
and function.
Neural Cell Fate Specification
How are neural progenitor cells specified for neuronal and glial fates? Our fate mapping studies revealed that spinal cord motor neurons and oligodendrocytes arise from distinct progenitor populations that express the transcription factor Olig2. Single cell RNA-seq then uncovered the molecular identities of those progenitors. We are now using single cell Multiome, genetic gain and loss-of-function manipulations, and fate mapping to identify the gene regulatory network that directs progenitor cells into the oligodendrocyte lineage. |
Developmental Myelination
Individual myelin sheaths formed by a single oligodendrocyte vary in number, length, and thickness and myelin sheath characteristics can be changed by neuronal activity. What are the molecular mechanisms that mediate myelin plasticity in response to activity? Current projects to answer this question include (1) investigating whether canonical postsynaptic factors determine myelination of specific axon classes, (2) testing the role of RNA localization and translation in nascent myelin sheaths, and (3) assessing contributions of the extracellular matrix to myelination. |
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Microglia and Neural Development
Microglia, the innate immune cells of the CNS, are well known for their roles in disease and injury but how they contribute to neurodevelopment remains poorly understood. Using timelapse imaging we discovered that microglia phagocytose individual myelin sheaths during normal development. We now have several lines of investigation aimed at learning how microglia identify myelin sheaths for removal, how microglia functions help shape the developmental myelination landscape, and how myelin-regulatory functions of microglia are altered by disease. |
Neural Disease
Developmental disorders of the nervous system can have devastating impacts on children and their caregivers. We are leveraging our knowledge of developmental mechanisms to investigate how genetic variation and environmental stressors impair brain development and function. Our current projects include Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome, Huntington's disease, TCF7L2-related neurodevelopmental disorder, and maternal nutritional deficiency.
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Maternal Nutrition and Brain Development
Poor maternal nutrition impairs infant brain growth and increases the risk of neurodevelopmental disorders. Yet we don’t understand how nutritional status impacts brain development at the cellular and molecular level. Addressing this mechanistic gap could inform maternal interventions that help prevent nutrition-related brain deficits and support lifelong cognitive health. We are currently using a combination of dietary and genetic manipulations to investigate how omega-3 fatty acid deficiency affects microglia and their dynamic interactions with oligodendrocytes and neurons.
image credits - Natalie Carey, Alex Hughes, Katie Yergert, Caleb Doll
