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Jeffrey Mumm , Ph.D.
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Assistant Professor Department of Cellular Biology and Anatomy
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Education and Training:
91-94 BS Biology University of Iowa
95-00 PhD Neuroscience Washington University
01-04 Postdoc Neural Circuitry Washington University
Biotech Industry Positions:
04-07 Research Director Cellular Regeneration Luminomics, Inc.
Academic Positions:
07-present Assistant Professor Circuitry Regeneration Medical College of Georgia
Awards & Honors:
1999 Viktor Hamburger Award for Excellence in Developmental Biology Research
2000 James L. O'Leary Prize for Research in Neuroscience
2001 Harold M. Weintraub Award for Excellence in Graduate Studies Research
2004 Olin Cup for Excellence in Entrepreneurial Business Development
Research Goals:
The long-term goals of my research program are to elucidate how neuronal circuits form, function, and regenerate. Special emphasis is placed on translating what is learned in the zebrafish model system during the course of these studies toward the development curative therapies for neurodegenerative conditions afflicting humans.
Neural Circuit Formation
My approach to studying how neural circuits form is to, at least initially, simply watch. Recent advances in high-resolution microscopy and transgenic labeling techniques have made it possible to perform time lapse imaging studies of cellular development. Due to the fact that fish eggs develop externally and fish larvae are highly transparent the zebrafish model provides an excellent system for studying vertebrate cellular development, directly in the living organism. This 4-dimensional approach – 3D imaging plus time – provides unprecedented access to how cells behave and interact during development. The movie below provides an example: a single retinal ganglion cell (RGC, yellow) neuron is seen at an early stage of development in the retina; dendritic outgrowths can be seen rapidly extending and retracting within the synaptic neuropil, the inner plexiform layer (IPL; blue “cloud”) of the retina, that this cell will ultimately innervate to form synaptic connections (5 min per frame, 30 min total, repeats 4 times).
Following descriptive studies, which establish how a given subset of neurons normally produces mature arbor patterns and/or how a given neural subscircuit forms (see below), manipulations of the microenvironment can be used to determine how the process is regulated. We are now beginning to test the requirement of specific cellular interactions, as well as several candidate molecular patterning cues, for their roles in establishing proper circuitry in the retina.
By differentially labeling separate neuronal subpopulations it is possible to view interactions that occur between synaptic partners as circuits are forming. The images below show the dendrites of individual RGCs (yellow) and the neurites of a subpopulation of retinal interneuron called amacrine cells (blue) interacting as they form highly stratified subcircuits in the inner plexiform layer of the retina.
These studies produced new insights into how neural circuits can form; dendrites appear to be capable of actively targeting their presynaptic partners. That is, amacrine cells formed stratified arbor structures at a time when RGC dendrites remained immature, undergoing dynamic rearrangements (as in the movie above) that suggest they are sampling the environment for patterning cues. Later, RGC dendritic arbors begin to stabilize as they co-stratify with pre-patterned amacrine neurites, their afferent target fields (see, Mumm et al., 2006). This finding has important implications for circuit regeneration. If dendrites can actively target appropriate partners – as has been previously shown for axons – it may be sufficient to stimulate the regeneration of, or transplant, specific neuronal subtypes lost to a given disease. Subsequent wiring could then result from active targeting mechanisms operable for both axonal and dendritic outgrowths (assuming proper wiring cues are present in the mature nervous system).
Neural Circuit Function
To study how neural circuits function (and can regenerate, see below) I have developed an inducible targeted cellular ablation system. Using this approach, individual neuronal subtypes can be targeted and eliminated thus disrupting specific neuronal subcircuits. Subsequent adaptations, for instance circuit remodeling, can be visualized using high-resolution time lapse microscopy (as above). In addition, changes in perceptive capacities and/or behaviors can be assessed in order to ascribe defined functions to specific subcircuits. Using this system, efforts will be made to dissect retinal neural circuitry in order to determine how visual information is processed within the eye.
Neural Circuit Regeneration
Zebrafish have a remarkable capacity for cellular regeneration that extends even to the nervous system. Because zebrafish are also amenable to large-scale genetic and chemical screens, an inducible targeted ablation platform can be used to investigate the genetic factors underlying the regeneration of specific cellular subtypes. Automated screening methods are being developed that will facilitate large-scale screens for mutations which disrupt the ability to regenerate specific neuronal subtypes. These “regeneration-deficient” mutants, in turn, will serve as neurodegenerative disease models in large-scale chemical screens aimed at discovering compounds which promote the regeneration of the targeted cell types. Moreover, identifying interacting “networks” of genes required for the regeneration of a given cell (i.e. the genes disrupted in regeneration-deficient mutants) will serve to “inform” the chemical screening process, allowing specific molecular pathways to be targeted and increasing the likelihood of success.
Techniques:
Molecular cloning; Promoter analysis; Microinjection; Transgenesis; Time Lapse Confocal Microscopy, Large-scale forward genetics; Large-scale chemical screens; High-throughput screen automation; Behavioral assays; Visual reflex assays; Immunocytochemistry.
Selected Publications:
Kay, J.N.*, Roeser, T.*, Mumm, J.S.*, Godinho, L.*, Mrejeru, A., Wong, R.O.L., and H. Baier (2004). Transient requirement for ganglion cells during assembly of retinal synaptic layers. Development, 131: 1331-1342 (*equal contribution).
Godinho, L., Mumm, J.S., Williams, P.R., Schroeter, E.H., Koerber, A., Seung W. Park, S.W., Leach, S.D., and R.O.L. Wong (2005). Targeting of amacrine cell neurites to appropriate synaptic laminae in the developing zebrafish retina. Development, 132: 5069-5079.
Mumm, J.S., Williams, P.R., Godinho, L., Koerber, A., Pittman, A.J., Roeser, T., Chien C.-B., Baier, H., and R.O.L. Wong (2006). In vivo imaging reveals dendritic targeting of laminated afferents by zebrafish retinal ganglion cells. Neuron, 52: 609-621.
Curado, S., Anderson, R.M., Jungblut, B., Mumm, J., Schroeter, E., and D.Y., Stainier (2007). Conditional targeted cell ablation in zebrafish: A new tool for regeneration studies. Developmental Dynamics, 236: 1025-1035.