Research Interests
Developmental Neurobiology: Axon Guidance, Forebrain Patterning, and Pituitary Developement
My laboratory uses zebrafish as a simple vertebrate system to study how the forebrain and pituitary gland develop,
and to investigate how axons are guided across the midline to form the forebrain commissures and optic chiasm.
Accessible and rapid early development, combined with beautiful imaging characteristics and the ability to
manipulate gene expression, make zebrafish a powerful model system for the study of early brain formation.
Pituitary Induction and Patterning
The vertebrate pituitary gland is the "master" endocrine gland and controls a wide range of metabolic functions,
from growth, to reproduction, to stress responses. The zebrafish is a relatively untapped resource in the study
of endocrine development, and has profound advantages for research into pituitary development. In particular, the
genetic and optical accessibility of the embryo makes it possible to observe and manipulate the earliest events
in pituitary formation (see time-lapse movie).
Importantly, pituitary structure is highly conserved across vertebrate species, making studies in zebrafish directly relevant to human development.
Our analysis of zebrafish forebrain mutants led to the discovery that the small protein Sonic Hedgehog
(Shh) is a critical player in the early induction of the pituitary placode, as well as in the differentiation
of a subset of endocrine cell types. This role for Shh is conserved across vertebrates, with defects in human
Shh signaling leading to congenital disorders affecting pituitary development. In addition, aberrant Shh signaling
in the adult pituitary is associated with common pituitary adenomas. A major project in the lab is to investigate
the cellular and molecular mechanisms by which Shh regulates this endocrine gland, both in the embryo and
post-embryonically. This research is aiding our understanding of human birth defects and is beginning to shed
light on how mis-regulation of Shh signaling can lead to pituitary tumors.
Axon and Glial Guidance in the forebrain
We continue to use the zebrafish achiasmatic mutants as tools for investigating the mechanisms that guide
axons across the midline of the forebrain. We recently showed that the belladonna (bel) mutation
affects the lhx2 gene. In both lhx2 and shh mutants, the axon growth substrate is
disrupted in specific ways, providing clues as to the axon guidance mechanisms that are required for proper
midline crossing. In particular, we have characterized a unique population of glial cells that spans the
midline just prior to axon crossing, and shown that this glial bridge is disrupted in the achiasmatic
mutants. We are currently investigating how these glial cells find their correct positions in the forebrain and how they subsequently help establish of the optic chiasm and forebrain commissures.
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Representative Publications
Devine, C.A., Sbrogna, J.L., Guner, B., Osgood, M., Shen, M-C., and Karlstrom, R.O. (In press.) A dynamic Gli code interprets
Hh signals to regulate induction, patterning, and endocrine cell specification in the zebrafish pituitary. Developmental Biology,
(accepted 11/4/08).
Guner, B., Ozacar, A.T., Thomas, J.E., and Karlstrom, R.O. 2008. Graded Hh and Fgf
signaling independently regulate pituitary cell fates and help establish the PD and PI of the zebrafish adenohypophysis. Endocrinology, 149(9): 4435-51.
Bergeron, S.A., Milla, L.A., Villegas, R., Shen, M-C., Burgess, S.M., Allende, M.L., Karlstrom, R.O., and Palma, V. 2008.
Expression profiling identifies
novel Hh/Gli regulated genes in developing zebrafish embryos. Genomics, 91(2): 165-77.
Guner, B. and Karlstrom, R.O. 2007. Cloning of zebrafish
nkx6.2 and a comprehensive analysis of the conserved transcriptional response to Hedgehog/Gli signaling in the
zebrafish neural tube. Mechanisms of Development, 7(5): 596-605.
Seth, A., Culverwell, J., Walkowicz, M., Toro, S., Rick, J.M., Neuhauss, S., Varga, Z., and Karlstrom, R.O. 2006.
belladonna/lhx2 is required for neural patterning and midline axon guidance in the zebrafish forebrain. Development, 133: 725-735.
Cerda, G.A., Thomas, J.E., Allende, M.A., Karlstrom, R.O., Palma, V. 2006.
Electroporation
of DNA, RNA, and morpholinos into zebrafish embryos. Methods, 39: 207-211.
Barresi, M.J., Hutson, L., Chien, C-B., and Karlstrom, R.O. 2005. Hedgehog regulated
Slit expression determines commissure and glial cell position in the zebrafish forebrain. Development, 132(16): 3643-56.
Vanderlaan, G.M., Tyurina, O.V., Karlstrom, R.O., and Chandrasekhar, A., 2005. Gli Function is
Essential for Motor Neuron Induction in Zebrafish. Developmental Biology, 282(2): 550-70.
Tyurina, O.V., Guner, B., Popova, E., Feng, J., Schier, A.F., Kohtz, J.D., and Karlstrom, R.O.
2005. Zebrafish Gli3 functions as both an activator and a repressor in Hedgehog signaling.
Developmental Biology, 277: 537-556.
Feng, J., White, B., Tyurina, O., Guner, B., Larson, T., Lee, H., Karlstrom, R. O.,
and Kohtz, J. 2004. Synergistic and antagonistic roles of the Sonic hedgehog N and C-terminal
lipids. Development, 131(17): 4357-70.
Sekimizu, K, Nishioka, N, Sasaki, H, Takeda, H, Karlstrom, R.O. and Kawakami, A. 2004.
The zebrafish iguana
locus encodes Dzip1, a novel zinc finger protein required for proper regulation of hedgehog signaling.
Development, 131: 2521.
Ungos, J.M., Karlstrom, R.O. , and Raible, D.W. 2003.
Hedgehog
signaling is directly required for the development of zebrafish dorsal root ganglia neurons. Development. 130: 5351-5362.
Sbrogna, J.L., Barresi, M.J.F., and Karlstrom, R.O. 2003. Multiple
roles for hedgehog signaling in zebrafish pituitary development. Developmental
Biology. 254(1): 19-35.
Karlstrom, R.O., Tyurina, O., Kawakami, A., Nishioka, N., Talbot,
W.S., Sasaki, H., and Schier, A.F. 2003.
Genetic
analysis of zebrafish gli1 and gli2 reveals and divergent requirements
for gli genes in vertebrate development. Development. 130:
549-1564.
Culverwell, J., and Karlstrom, R.O. 2002.
Making the connection: Retinal axon
guidance in the zebrafish. Sem. Cell and Developmental Biol. 13(6): 497-506.
diIorio, P.J., Moss, J.B., Sbrogna, J.L., Karlstrom, R.O., and
Moss, L.G. 2002.
Sonic
hedgehog Is Required Early in Pancreatic Islet Development. Developmental
Biology, 2002 Apr 1 244(1): 75-84.
Kondoh, H., Ukhikawa, M., Yoda, H., Furutani-Seiki, M., and Karlstrom, R.O. 2000.
Zebrafish mutations in gli-mediated hedgehog signaling lead to lens transdifferentiation
from the adenohypophysis anlage. Mechanisms of Development 96: 165-174.
Karlstrom, R.O., Talbot, W.S. and Schier, A.F. 1999.
Synteny cloning
of zebrafish you-too: Mutations in the hedgehog target gli2 affect ventral
forebrain patterning. Genes and Development 13: 388-393.
Karlstrom, R.O., Trowe, T. and Bonhoeffer, F. 1997. Genetic analysis of
axon guidance in the zebrafish. Trends in Neurosciences 20: 3-8.
Karlstrom, R.O. and Kane, D.A. 1996.
A time-lapse
flip-book of zebrafish development. Development 123: 2-460.
Karlstrom, R.O., et al. 1996. Zebrafish mutations affecting retinotectal axon pathfinding. Development 123: 427-438.
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