Mumm, Jeff Mumm Lab Medical College of Georgia Dept. of Cellular Biology and Anatomy 1459 Laney Walker Blvd., CB-2917 Augusta, GA 30912-2000 USA

RESEARCH INTERESTS

The research being pursued in my lab concerns the formation, function, and regeneration of neural circuitry. Neuronal development is monitored directly in living zebrafish using time lapse imaging. Individual neurons and neuronal subpopulations are visualized using fluorescent cellular reporters (e.g. GFP) in combination with high-resolution microscopy. Apposing neuronal subpopulations, e.g. pre- and postsynaptic partners, are simultaneously imaged using complimentary fluorescent reporter color variants. This simple strategy allows us to assess how neural circuits are assembled in wildtype versus genetically manipulated embryos and larvae.

To investigate circuit function (and regeneration, see below), I and my collaborators have developed a simple method of targeted cellular ablation based on transgenic expression of the pro-drug converting enzyme, nitroreductase (NTR). NTR-expressing neurons can be eliminated, thus disrupting specific neuronal subcircuits, by exposing fish to pro-drug substrates such as metronidazole. NTR converts pro-drugs into cytotoxins, thereby killing NTR-expressing cells. Subsequent adaptations, for instance circuit remodeling, can be visualized using high-resolution time lapse microscopy (as above). In addition, changes in behavioral outputs can be assessed in order to ascribe specific functions to discrete 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.

Zebrafish have a remarkable capacity for cellular regeneration that extends to the nervous system. Because zebrafish are also amenable to large-scale genetic and chemical screens the NTR-based cell ablation platform can be used to discover factors required for the regeneration of specific cellular subtypes. Automated screening methods are being developed that will facilitate genetic screens for regeneration deficient mutants and subsequent small molecule screens aimed at identifying regeneration-promoting compounds. By identifying genes required for the regeneration of specific cells, insights will be gained regarding how adult stem cell populations are regulated. In addition, such insights will serve to inform the small molecule screening process. The NTR-based system can be targeted to any transgenically definable cellular subpopulation and should thus be of general interest to the zebrafish research community.

A company formed around the targeted cellular ablation technology described, Luminomics Inc. (www.luminomics.com), is deriving NTR-expressing enhancer trap lines. These tools should be of use in assessing cell function and as a means to promote regenerative research from a multitude of cell and tissue type perspectives.

Journal Article:

Saxena M.T., Schroeter E.H., Mumm J.S., Kopan R. (2001). Murine Notch homologs (N1-4) undergo presenilin-dependent proteolysis. Journal of Biological Chemistry, 276: 40268-40273.

Mumm, J.S., Schroeter, E.H., Saxena, M.T., Griesemer, A., Tian, X., Pan, D.J., Ray, W.J., and Kopan, R. (2000). A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol. Cell 5, 197-206.

Huppert, S., Le, A., Schroeter, E., Mumm, J.S., Saxena, M.T., Milner, L., and R. Kopan (2000). Embryonic lethality in mice homozygous for a processing deficient Notch1 allele. Nature 405, 966-970.

Ray, W.J., Yao, M., Mumm, J., Schroeter, E.H., Saftig, P., Wolfe, M., Selkoe, D.J., Kopan, R. and A. M. Goate (1999). Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch. J. Biol. Chem., 274, 36801-36807.

De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J.S., Schroeter, E.H., Schrijvers, V., Wolfe, M.S., Ray, W.J., Goate, A., and R. Kopan (1999). A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 398: 518-522.

Ray, W.J., Yao, M., Nowotny, P., Mumm, J., Zhang, W., Wu, J.Y., Kopan, R., and A. M. Goate (1999). Evidence for a physical interaction between Presenilin and Notch. Proc. Natl. Acad. Sci. USA. 96: 3263-3268.

Calof, A.L., Mumm, J.S., Rim, P.C, and J. Shou (1998). The neuronal stem cell of the olfactory epithelium. Jour. Neurobio. 36: 190-205.

Mumm, J.S., Shou, J. and A.L. Calof (1996). Colony-forming progenitors from mouse olfactory epithelium: Evidence for feedback regulation of neuron production. Proc. Natl. Acad. Sci. USA. 93: 11167-11172.

Calof, A.L., Hagiwara, N., Holcomb, J., Mumm, J.S. and J. Shou (1996). Neurogenesis and cell death in olfactory epithelium. Jour. Neurobio. 30: 67-81.

Gordon, M.K., Mumm, J.S., Davis, R.A., Holcomb, J.D. and A.L. Calof (1995). Dynamics of MASH1 expression in vitro and in vivo suggest a non-stem cell site of MASH1 action in the olfactory receptor neuron lineage. Mol. Cell. Neuro. 6: 363-379.

Holcomb. J.D., Mumm, J.S., and A.L. Calof (1995). Apoptosis in the neuronal lineage of the mouse olfactory epithelium: Regulation in vitro and in vivo. Develop. Bio. 172: 307-323.


Book Chapters and Reviews:

Mumm, J.S. and C. Lohmann (2006). Dendritic growth. In: Retinal Development, E. Sernagor, S. Eglen, W. Harris, and R. Wong, eds. (Cambridge University Press, New York), pp. 242-264.

Mumm, J.S., Godinho, L., Morgan, J.L., Oakley, D.M., Schroeter, E.H., and R.O.L. Wong (2005). Laminar circuit formation in the vertebrate retina. In: Development, Dynamics and Pathology of Neuronal Networks: From Molecules to Functional Circuits, Progress in Brain Research, vol. 147, J. van Pelt , M. Kamermans, C.N. Levelt, A. van Ooyen , G.J.A. Ramakers, P.R. Roelfsema, eds. (Elsevier BV, Amsterdam, The Netherlands), pp. 155-169.

Lohmann, C., Mumm, J., Godinho, L., Schroeter, E., Stacy, R., Wong, W.T., Oakley, D., and Wong, R.O.L. (2005). Live imaging of the developing retina. In: Imaging in Neuroscience and Development, R. Yuste, and A. Konnerth, eds. (Cold Spring Harbor Laboratory Press), pp. 171-183.

Kopan, R., Huppert, S., Mumm, J.S., Saxena, M.T., Schroeter, E.H., Ray, W.J., and Goate, A. (2001). The NEXT step in Notch processing and its relevance to Amyloid Precursor Protein. In: Neurodegenerative disorders: loss of function through gain of function, K. Beyreuther, Y. Christen, and C.L. Masters, eds. (Springer-Verlag, New York), pp. 119-128.

Mumm, J.S., and R. Kopan (2000). Notch signaling: From the outside in. Develop. Bio. 228: 151-165.

Calof, A.L., Mumm, J.S., Rim, P.C, and J. Shou (1999). In vitro analysis of neuronal progenitors from mouse olfactory epithelium. In: The Neuron in Tissue Culture (L. Haynes, ed.) Wiley, Chichester.

Calof, A.L., Rim, P.C, Askins, K,J., Mumm, J.S., Gordon, M.K., Iannuzzelli, P., and J. Shou (1998). Factors regulating neurogenesis and programmed cell death in mouse olfactory epithelium. In: Olfaction and Taste XII (C. Murphy, ed.) Ann. N.Y. Acad. Sci. 855: 226-229.

Calof, A.L., Holcomb, J.D., Mumm, J.S., Hagiwara, N., Tran, P., Smith, K.M., and D. Shelton (1996). Factors affecting neuronal birth and death in the mammalian olfactory epithelium. In: Growth Factors as Drugs for Neurological and Sensory Disorders. Wiley, Chichester, (Ciba Foundation Symposium No. 196): 188-210.

Calof, A.L., Adusumalli, M.D., Dehamer, M., Guevara, J.L., Mumm, J.S., Whitehead S.J. and A.D. Lander (1994). Generation, differentiation, and maturation of olfactory receptor neurons in vitro. In: Olfaction and Taste XI (K. Kurihara, N. Suzuki, H Ogawa, eds.) Tokyo, Springer-Verlag: 36-40.