Porter room A445C
Molecular genetics of mouse neural development.
In one of the crowning achievements of evolution, the network of cells we call the nervous system can modify its output based upon inputs from the outside world, thereby altering the behavior of the organism. Unfortunately, disease can lead to dysfunction and degeneration of the nervous system, leading to consequences that are readily apparent in an aging human population suffering increasingly from afflictions including Alzheimer's, Parkinson's, and Huntington's diseases. What are the molecular mechanisms that underlie the development, function, and deterioration in disease of this extraordinary cellular network? The nervous system is formed by a regulated sequence of events: 1. Controlled proliferation of neuronal precursors 2. Specification of fates for the precursors 3. Process outgrowth, formation of synaptic connections, cell death 4. Ongoing plasticity of synaptic connections Cell-cell interactions are known to play a critical role in each of these steps. Among the mediators of such interactions, a family of growth factors, the neurotrophins, is particularly interesting. This family includes the prototypical neurotrophin nerve growth factor (NGF) as well as brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5. Each neurotrophin is essential for the survival of a subsets of neuron types. Neurotrophins can also alter the structure of axons and dendrites, and can modulate the strength of synaptic connections. Of particular interest, the expression and release of BDNF is modulated by neural activity, suggesting that it may be one of the critical links between experience and the permanent changes in the nervous system that must underlie long-term memory. My laboratory studies the functions of neurotrophic factors in development and their relevance to neurodegenerative disease using a blend of transgenic mouse technology and anatomical, cell biological, and molecular techniques. We have used powerful conditional "gene knockout" techniques involving the cre/lox recombinase system to create mice that lack neurotrophic factors only in a specific tissue. This allows us to dissect functions in a specific tissue and/or at a specific developmental stage. We have focused primarily on the neurotrophin BDNF, studying its functions in the brain and peripheral nervous system. These studies showed that BDNF is particularly important in stabilizing the dendritic structure of neurons after this structure initially develops. Interestingly, this may relate to a requirement for BDNF in the formation or stabilization of many synapses. Recently, we have identified compelling parallels between our mice lacking BDNF and human neurodegenerative diseases including Parkinson's and Huntington's diseases. Thus, we believe that further studies using these mice will be useful in identifying pathways that may prove to be useful targets in treating these diseases.
Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor.
Baquet, ZC, Gorski, JA, and Jones, KR J Neurosci, 24(17):4250-8. 2004
Neurotrophin-3 is expressed in a discrete subset of olfactory receptor neurons in the mouse.
Vigers, AJ, Bottger, B, Baquet, ZC, Finger, TE, and Jones, KR J Comp Neurol, 463(2):221-35. 2003
Brain-derived neurotrophic factor is present in adult mouse taste cells with synapses.
Yee, CL, Jones, KR, and Finger, TE J Comp Neurol, 459(1):15-24. 2003
The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3.
Klein, R, Nanduri, V, Jing, SA, Lamballe, F, Tapley, P, Bryant, S, Cordon-Cardo, C, Jones, KR, Reichardt, LF, and Barbacid, M Cell, 66(2):395-403. 1991
The trk tyrosine protein kinase mediates the mitogenic properties of nerve growth factor and neurotrophin-3.
Cordon-Cardo, C, Tapley, P, Jing, SQ, Nanduri, V, O'Rourke, E, Lamballe, F, Kovary, K, Klein, R, Jones, KR, and Reichardt, LF Cell, 66(1):173-83. 1991