Developmental Neuroscience

Forebrain Development Memory, higher order cognitive functions and directed movement are controlled by the forebrain, which includes the cerebral cortex, hippocampus, striatum, and pallidum. Improper development of these structures underlies many devastating childhood disorders such as excencephaly, holoprosencephaly and autism. In an effort to understand both normal and perturbed development of the cortex, Tarik F. Haydar, PhD, uses multiphoton microscopy to perform long-term live imaging of cortical progenitor cells in embryonic brain tissue slices. His objective is to understand how cell cycle and lineage progression is regulated during cortical development. A particular focus is on the mechanisms of mitotic spindle alignment and rotation during cortical cell division and its role in generating distinct precursor subtypes. Additionally, he is studying embryonic development in Ts16 and Ts65DN mice, two animal models of Down syndrome. Joshua Corbin, PhD, studies the genetic and cellular basis of the development of the mammalian amygdala. The amygdala is a major component of the brain's limbic system, a functionally interconnected set of forebrain structures that also includes the hippocampus, prefrontal and cingulate cortices, hypothalamus, and nucleus accumbens. Despite an extensive understanding of amygdala function and anatomy, currently little is known regarding the embryonic development of this complex structure. Using the mouse as an experimental model, the Corbin lab is examining how migrating neural progenitor cells in the developing telencephalon contribute to neuronal cell diversity in the mature amygdala and how these cells become wired together to form mature brain circuits. The ultimate goal of the studies in the Corbin lab is to understand the link between developmental events and the assembly of the mature amygdala at a genetic, cellular, structural and functional level. From these studies, the hope is to not only elucidate the normal mechanisms of brain development, but also gain a greater understanding of the etiology of developmental disorders, such as autism, in which development of the amygdala is affected. David M. Panchision, PhD, is using transgenic mice, flow cytometry, explant and in vitro methods to investigate how different lineages are controlled in both the cortex and the lateral ganglionic eminence, the region that gives rise to the adult striatum and may also give rise to adult stem cells.

Myelin and White Matter Development Specialized cells called oligodendrocytes produce myelin sheaths that surround and insulate axon projections of neurons, thereby promoting the propagation of electrical impulses throughout the brain. The great abundance of myelination along axon tracts makes these brain areas appear white, hence the name "white matter." A number of diseases and some types of injury lead to the degeneration of oligodendrocytes and myelin sheaths. Children's researchers are interested in treating these disorders by preventing or repairing damage to oligodendrocytes. An understanding of oligodendrocyte development is critical to these efforts. Gallo Vittorio, PhD, is studying mutant mice to understand the role of endothelins in regulating the migration and maturation of oligodendrocytes. Dr. Gallo and Tarik F. Haydar, PhD, are collaborating on two photon microscopy imaging studies on oligodendrocyte migration. Dr. Gallo and Li-Jin Chew, PhD, are collaborating to identify transcription factors with novel roles in oligodendrocyte differentiation and myelination using microarray and functional analysis. Dr. Chew is also studying oligodendrocyte progenitor proliferation and differentiation in response to cytokines. Dr. Chew and Michael Bell, MD, are using in vitro assays and animal models to study disorders of white matter development.

Morphogen Signaling in the Nervous System Morphogens are secreted factors that work in a concentration-dependent manner to control the shape, size and identity of tissues in the developing embryo. Disruptions in morphogen signaling early in development can lead to neural tube defects such as excencephaly and holoprosencephaly, while later disruption can lead to other CNS disabilities or even brain tumors. Bone morphogenetic proteins (BMPs) are an important class of morphogens that control precursor cell proliferation, survival and differentiation during embryonic development and into adulthood. David M. Panchision, PhD, is using in vitro techniques as well as transgenic and knockout mice to study the intracellular mechanisms that cause neural stem cells and committed progenitor cells to respond in different ways to BMPs.

Neurotransmitter Regulation Communication between neurons involves molecules called neurotransmitters that are secreted by one neuron and rapidly received by another. Regulation of neurotransmitter activity occurs at the level of synthesis, storage, release, reception, and termination of action. Margaret L. Sutherland, PhD, uses mouse gain- and loss-of-function mutants to investigate this final step in the regulation of glutamate, the predominant excitatory neurotransmitter in the CNS. Glutamate is removed from the synapse by several glutamate transporter proteins, most of which are localized to astroglial cells. Dr. Sutherland’s work focuses mainly on this site of transport. Additionally, she is studying the role of potassium channels in regulating the propogation of action potentials. These studies have important implications for the etiology and treatment of epilepsy and amyotrophic lateral sclerosis (ALS).

Ion Channel Regulation in Glia Recent evidence indicates that glia cells are not simply passive support cells for neurons but have very dynamic properties, including electrical activity. Vittorio Gallo, PhD, and Ramesh Chittajallu, PhD , are investigating the changing electophysiological properties of glia cells as they mature. They are performing in vitro and in vivo over-expression studies of potassium and glutamate channels to determine the role that subunit composition plays in oligodendrocyte maturation. This functional analysis will provide insight into the relationship between improper oligodendrocyte maturation and CNS developmental disorders. Contact Information: Vittorio Gallo, PhD Children’s Research Institute Center for Neuroscience Research Children's National Medical Center 111 Michigan Avenue, NW Washington, DC 20010 202-476-4996 202-476-4988 fax vgallo@cnmc.org