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, cell death
4.terminal differentiation of the remaining cells
The resulting network of cells is capable of modifying its
behavior based upon stimuli from the outside world, thereby
altering the behavior of the organism. What are the molecular
mechanisms that underlie the development, function, and deterioration
in disease of this extraordinary cellular network? It is now
clear that cell interactions have a critical role in both
the development and function of the nervous system. What molecules
convey these signals? A family of polypeptide hormones, the
neurotrophins, are members of the nerve growth factor [NGF]
family) are of particular interest because of their striking
activities on cultured neurons, supporting their survival
and process outgrowth. This family includes the prototypical
neurotrophin NGF as well as brain-derived neurotrophic factor
(BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5.
Powerful techniques have been developed for the generation
of mice having genetic modifications created in vitro ("knock-out
mice") in embryonic stem cells. Dr. Jones˙ laboratory uses
these techniques to study gene function in the development
of the mammalian nervous system. He now knows, from the study
of mouse mutants, that neurotrophins are absolutely required
for the survival and development of specific neuronal cell
types. The study of null mutations in mice has limitations,
particularly when the mutation results in lethality at an
early stage of the life cycle. One very exciting approach
Dr. Jones has pursued to circumvent these problems is to create
mice that have a mutation only in a specific tissue (genetic
mosaics) through the use of the cre/lox recombinase system.
This approach will be quite valuable in dissecting gene functions
in a specific tissue or at a specific developmental stage
where null mutations would be uninformative or lethal. Initially,
Dr. Jones has focused on the neurotrophin BDNF, studying its
functions in the brain and peripheral nervous system. In the
course of this work, he has developed valuable strains of
mice that he will also use in the analysis of other genes
relevant to neural development through the generation of tissue-specific
Bennett, J. L. S.R. Zeiler and K.R. Jones. (1999) Patterned
Expression of BDNF and NT-3 in the Retina and Anterior Segment
of the Developing Mammalian Eye. Investigative Ophthalmology
and Visual Science. 40:2996-3005.
Vigers, A.J., Z.C. Baquet and K.R. Jones. (2000) Expression
of neurotrophin-3 in the mouse telencephalon: Insights from
a Targeted lacZ Reporter. J. Comp. Neurol. 416:398-415.
Gorski, J.A., Talley, T., Qiu, M., Puelles, L., Rubenstein,
J.L.R., and K.R.
Jones (2002) Cortical excitatory neurons and glia, but not
GABAergic neurons, are produced in the Emx1-expressing lineage.
J. Neuroscience 22(15): 6309-14.
Gorski, J.A., Zeiler, S.R., Tamowski, S., and K.R. Jones
(2003) BDNF is required for the maintenance of cortical dendrites.
J. Neuroscience 23(17):6856-65
Gorski, J.A., Balogh, S.A., Wehner, J.M., and K.R. Jones
(200X) Learning deficits in forebrain-restricted BDNF mutant
mice. Neuroscience In press