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Lisa Maves A.B.,
Washington University, 1992 Ph.D.,
University of Washington, 1997 Postdoctoral Fellow,
Kimmel Lab |
Research Interests My research focuses on
understanding how the vertebrate hindbrain develops. The zebrafish hindbrain is an
important model for nervous system development for many reasons. As in other vertebrates, including
humans, the zebrafish hindbrain is subdivided along the anterior-posterior
axis into seven segments, or rhombomeres. Each rhombomere acquires a segment-specific identity, and
sets of neurons, many of which are individually identifiable in zebrafish,
are segmentally reiterated at specific positions within each rhombomere. I want to understand hindbrain
development from the earliest steps of generating the proper number of
hindbrain segments, to how specific neurons acquire their proper identities
and positions within each segment.
The ability to use genetics, time-lapse imaging, transplantation and
pharmacological treatments makes zebrafish an extremely powerful organism
with which to address these questions.
Because hindbrain development is so conserved, zebrafish can be used
as a model for understanding human hindbrain development and, potentially,
disorders associated with the brain stem. Hox genes are critical regulators of hindbrain segment
identity. I am studying upstream
initiation of Hox gene expression
in the hindbrain, as well as factors that maintain Hox expression.
I am currently focused on three projects: How FGF and RA signaling act upstream of Hox genes, How chromatin modification maintains Hox expression, and How these signaling pathways and Hox genes interact to control neuronal organization in
the hindbrain. Current
Projects FGF and RA signaling
upstream of Hox
expression I demonstrated a critical
role for signaling between rhombomeres through the discovery that rhombomere
4 (r4) functions as a hindbrain organizing center (Maves et al., 2002). Two Fibroblast Growth Factor signals,
FGF3 and FGF8, which are expressed early in r4, are together required for the
specification and growth of, and Hox gene expression in, r5 and r6. r4 cells have organizing activity and
can induce r5/6 development at ectopic positions, and this activity is
mediated by FGF signaling.
Further, I have found that FGF signaling from mesendoderm during
gastrulation activates early Hox gene expression in the hindbrain, upstream of r4 FGF
expression. I have thus
identified dual, sequential roles for FGF signaling in promoting Hox expression and hindbrain
development: an early role from the mesendoderm, and a later role from within
the neuroectoderm. I have also
found that FGF and retinoic acid (RA) signaling synergistically interact to
promote development of the posterior hindbrain (Maves and Kimmel, 2004). Maintenance of Hox expression in the hindbrain Together with Craig Miller,
we have found a new factor, Moz, critical for maintaining Hox gene expression in the
hindbrain. The zebrafish moz mutant
was discovered by Craig Miller in the Kimmel lab because it causes a homeotic
transformation of the second pharyngeal arch into the first arch. I showed that Hox expression in the hindbrain and
neural crest initiates in moz mutants but is not maintained. Moz encodes a histone
acetyltransferase, and this activity is critical for proper Hox
maintenance. This work thus
reveals a new factor essential for maintenance of cell fate and Hox expression (Miller et al., 2004). Regulation of
hindbrain neuronal positioning To identify additional,
perhaps novel, genes whose functions are required for hindbrain patterning, I
have performed a genetic screen based on phenotypes similar to those caused
by loss of FGF signaling, including characteristic defects in brain and ear
shape and neuronal patterning. I
have recovered eight mutant lines that show such defects and thus far have
focused on two of these lines. apex mutants, named for the
characteristic lump in the hindbrain, show particularly severe defects in
neuronal organization and morphologically resemble embryos with loss of
FGF3. apex; fgf8 double mutant embryos show
enhanced phenotypes that resemble loss of both FGF3 and FGF8, confirming a
strong genetic interaction between and apex and fgf8. I am positionally cloning apex, which promises to identify a new
critical component of FGF signaling in the hindbrain. A second mutant line from my screen
shows defects in the migration of the facial motor neurons: these cells normally migrate from r4
to r5 and r6, but fail to do so in this mutant. This mutant genetically interacts with other signaling
pathways known to affect facial motor neuron migration, including FGF and Wnt
signaling. Further
characterizations of the mutant lines identified in my screen are
ongoing. Teaching Each year I give a lab
and lecture in Chuck Kimmelıs Vertebrate Neuroanatomy course in the
University of Oregon Department of Biology. We talk about the segmental organization of hindbrain
neurons, the molecular genetics of hindbrain development, and a variety of
current techniques that are used to identify specific hindbrain neurons in
zebrafish. A pdf file of the lab
exercise is available: Identifying hindbrain neurons in zebrafish. Last revised: September 30, 2003 Copyright 2003 Lisa Maves |
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