RESEARCH
Building a nervous systems requires both the specification and maturation of diverse neuron types. Most post-mitotic neurons are specified in a brief window of time during embryonic/fetal development, but they continue to mature for weeks in mice and years in humans. For example, even though motor neurons are specified early during embryonic development, motor behaviors such as posture control, crawling, walking, and running, gradually mature over a span of years during postnatal life. During this prolonged period of maturation, neurons undergo dramatic changes in morphology, electrophysiology, gene expression, and chromatin structure as they integrate into circuits and become functionally mature.
Compared to our understanding of cell-type specification, the regulatory mechanisms that orchestrate maturation of post-mitotic neurons remain poorly understood. This discrepancy is also apparent in cell culture studies - while diverse neuron types can be efficiently differentiated from stem cells, culture systems do not recapitulate full neuronal maturation. Studying maturation is therefore crucial for understanding how adult nervous systems develop, generating mature neurons in culture, and mechanistically understanding diseases such as schizophrenia, Alzheimer’s, Parkinson’s, and Amyotrophic Lateral Sclerosis (ALS), which specifically affect maturing or mature neurons.
QUESTIONS AND PROJECTS
We are excited to understand how diverse neuron types undergo cell type specific gene expression and chromatin changes during maturation and to study how these changes contribute to functional maturation of the nervous system and neurological diseases.
We will begin by diving into the following topics:
In vivo maturation of diverse neuron types- What are the developmental principles that dictate the progression of maturation in neurons? Are regulators shared across the nervous system or are they cell type specific?
In vitro maturation of motor neurons- How do we manipulate stem cell-derived motor neurons to generate more mature, in vivo-like neurons in culture? Do similar methods work for other neuron types?
Maturation and disease- How do gene expression changes contribute to the adult specificity of neurological diseases?
We will combine strengths of in vivo and in vitro systems and use genomic, genetic, and computational methods to answer these questions.
PAST WORK
As a postdoc, I used spinal motor neurons as an entry point to begin dissecting how neuronal maturation is regulated in mice, and which aspects of maturation can be recapitulated in culture. By using genomics and computational approaches, I found that the transcriptional landscape in in vivo spinal motor neurons is highly dynamic from embryonic till juvenile ages, coinciding with functional maturation of motor behavior. We identified a switch in the transcriptional program during maturation and found that manipulation of this program results in reduction of pathologies associated with the adult onset disease ALS. In addition, we found that motor neurons differentiated from both mouse and human stem cells can partially recapitulate in vivo-like maturation in culture, paving the way for functional testing of missing regulators and generating more adult-like cells in vitro.