Anatomy, Physiology & Genetics (APG)
Uniformed Services University of the Health Sciences
4301 Jones Bridge Road
Bethesda, Maryland 20814
Martin Doughty, Ph.D.
Associate Professor Anatomy, Physiology and Genetics
- University College London, 1995
Current lab members
(left to right, from upper row)
Kryslaine Radomski and
We are interested in understanding the mechanisms that regulate mammalian neurogenesis. Current research projects focus on two topics: 1) transcription factor programs in developmental neurogenesis, organization and function of the cerebellum; 2) epigenetic regulation of neurogenesis in the adult subventricular zone. The laboratory uses multi-disciplinary approaches including conditional gene fate mapping and gene targeting, molecular biology, cell culture, histology, confocal imaging, stereology and mouse behavior testing.
Developmental Neurogenesis in the Cerebellum
A major challenge to understanding the signals that control neurodevelopment is the sheer numbers and intricacy of neuronal organization in the brain. While the functional organization of the cerebellum is as complicated as elsewhere in the brain, there is a simplifying structural plan that suggests the possibility of truly understanding how this part of the brain is formed.
Our goal is to identify the signaling pathways that generate the cellular and functional specificity of the cerebellum. Neurons are generated from two germinative zones in the developing cerebellum, the rhombic lip and ventricular zone. These zones are defined by distinct basic helix-loop-helix (bHLH) transcription factor activities and cell fate mapping and gene deletion studies demonstrate a requirement for bHLH gene activity in the specification of cerebellar cell types.
We investigate bHLH gene function in mouse cerebellar development using transgenic mice technologies to label or delete gene activity in mice. Conventional and conditional gene deletion strategies are used to determine the role of bHLH transcription factors during pre- and postnatal mouse development. The consequences of loss of gene function on cerebellar anatomy and motor behaviors controlled by this part of the brain are measured. Our objective is to determine the relationship between genetic determination programs in development and adult cerebellar organization and motor behaviors in mice. Understanding the genetic link between brain morphogenesis, function and behaviors is a fundamental goal of neuroscience.
Adult Neurogenesis and Traumatic Brain Injury
An estimated 230,000 Americans are hospitalized and survive a traumatic brain injury (TBI) each year. Tragically, 80,000 to 90,000 of these survivors will be left with long-term impairments and millions of Americans are currently living with TBI-related disabilities.
Clearly current therapies to treat TBI have not been effective in restoring many brain functions lost to injury and new strategies are required. Injury-induced neurogenesis offers some potential in the restoration of function. TBI activates quiescent neural stem cells to increase neurogenesis in the brain but the interaction between injury and neurogenesis is insufficiently understood to exploit this connection in therapies.
A critical but unexplored link between injury and neurogenesis is epigenetics. Epigenetic mechanisms are key regulators of physiological and pathological adult neurogenesis and yet their role in injury-induced neurogenesis is unknown. Our long-term goal is to understand the contribution of epigenetic regulators to injury-induced neurogenesis following focal head trauma.
The lab currently focuses on the role of histone demethylase enzymes in regulating physiological and injury-induced neurogenesis in the subventricular zone of adult mice. Histone demethylases dynamically remove methyl groups from lysine residues of histone proteins, a reaction that is associated with the epigenetic regulation of gene expression and cell fate.
Our research hopes to provide new insight into epigenetic mechanisms controlling injury-induced neurogenesis. Epigenetic regulators are enzymatic in nature and coordinate multiple gene targets making them highly amenable to therapeutic targeting. Our efforts are ultimately directed at developing interventional epigenetic approaches to promote cell replacement in the treatment of brain trauma.