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 JAMES D. LAUDERDALE
Assistant
Professor
Ph.D., 1992
Purdue University, West Lafayette, IN
RESEARCH
One of
the major challenges in neurobiology is understanding the cellular and
molecular mechanisms underlying development of the vertebrate central nervous
system (CNS). Research in our laboratory seeks to elucidate these mechanisms
by studying development of the vertebrate forebrain and visual system. We
study these systems by taking advantage of mutations that affect development
of the brain and eye in humans, mice, and zebrafish. Because genetic
approaches do not rely on previous assumptions, details about the mechanisms
mediating development of the visual system and forebrain can be uncovered
that might not be identifiable using other means.
GENES
INVOLVED IN EYE DEVELOPMENT
We are currently studying aniridia in humans and the Small eye trait
in rodents. Aniridia is a congenital inherited malformation of the eye that
occurs in approximately one-in-sixty-thousand babies each year. Individuals
afflicted with this disease typically feature severe hypoplasia of the iris
and may have associated defects including corneal opacification, cataracts,
and hypoplasia of the ciliary body and retina. This combination of ocular
defects results in poor visual acuity early in life and can lead to
blindness. Small eye is the mouse model for aniridia. Aniridia and Small
eye are caused by mutations in the PAX6 gene.
PAX6, a
paired-box transcription factor, is important for development of the eye,
forebrain, and subsets of neurons within the brain and spinal cord.
Heterozygous loss-of-function PAX6 mutations cause eye malformations
in mammals. Homozygous mutations result in absence of the eyes and nose, loss
of forebrain structures, disruption of axon tracts, abnormal neuronal
migration, and misspecification of neurons.
Although
mutations in the PAX6 gene cause aniridia, there are cases in which
the PAX6 gene is unaffected. We have identified a novel gene,
tentatively named La Femme d'� Cot� (LFDC), that is disrupted
in some of these cases. We subsequently identified this gene in rodents,
zebrafish, Drosophila, and C. elegans. In mice, Lfdc is
expressed both in the developing eye and in discrete domains within the
developing CNS. This expression pattern suggests that, like Pax6, Lfdc
may have multiple roles in neural development, although its molecular
function is unknown. We are currently investigating the role of Lfdc
during embryonic development.
IDENTIFYING
GENES DOWNSTREAM OF PAX6
Although Pax6 is important for several aspects of CNS development, little is
known about the identity of the genes that are regulated by Pax6�genes likely
to be important for development of the eye and forebrain. To identify such
genes, we have created libraries likely to contain genes regulated by Pax6
and are currently testing candidate clones. This work is being conducted in
collaboration with Drs. Nadean Brown (Northwestern University Medical School)
and Grant Mastick (University of Nevada, Reno).
ZEBRAFISH:
A USEFUL VERTEBRATE FOR STUDYING EARLY BRAIN DEVELOPMENT
Zebrafish embryos are well-suited for detailed studies of the mechanisms
underlying development of the forebrain because they develop rapidly, are
transparent, and have a relatively simple, extensively characterized nervous
system. These characteristics facilitate visualization of developing brain
regions, including specific neurons and their axons, in both living and
histologically prepared embryos. Additionally, zebrafish embryos can be
manipulated experimentally by ablation or transplantation of a single or a
small group of cells and genetically by both mutagenesis and by the
generation of transgenic animals.
Our
long-term goal is to develop therapies that can correct genetic and acquired
damage to the CNS. Understanding the basic developmental mechanisms by which
this system is formed and maintained will provide the insights necessary for
obtaining this goal.
SUPPORT STAFF
REPRESENTATIVE PUBLICATIONS
Lauderdale, J.D., E.R. Oliver, and
T.M. Glaser. "LFDC, a novel gene expressed in the developing eye, is
deleted in a subset of aniridic patients." Manuscript in preparation.
Lauderdale,
J.D., J.S. Wilensky, D.S. Walton, and T.M. Glaser. "Aniridia-associated
deletions distal to the PAX6 gene extinguish PAX6
expression." Submitted.
Lauderdale,
J.D., S.K. Pasquali, and J.Y. Kuwada. "Expression and regulation of a
neogenin gene in zebrafish embryos." Submitted.
Lauderdale,
J.D., S.K. Pasquali, R. Fazel, F.J.M. van Eeden, H.E. Schauerte, P. Haffter,
and J.Y. Kuwada. (1998) "Regulation of netrin-1a expression by hedgehog
proteins." Mol. Cell. Neuro. 11(4):194-205.
Lauderdale,
J.D., N.M. Davis, and J.Y. Kuwada. (1997) "Axon tracts correlate with
netrin-1a expression in the zebrafish embryo." Mol. Cell. Neuro.
9(4): 293-313.
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