Email: karlstrom@bio.umass.edu
R. Karlstorm Biology Web Site
Karlstrom Lab Homepage
Zebrafish Movie

Ph.D.: University of Utah
Postdoctoral Training: Max-Planck-Institute, Tubingen, Germany; Skirball Institute, New York University School of Medicine

Developmental Neurobiology: Axon Guidance, Forebrain Patterning, and Pituitary Development

As the brain develops neural tissue is precisely patterned to form discreet functional domains, then neurons extend axons over relatively vast distances to connect these different brain regions. My laboratory uses zebrafish as a simple vertebrate system to study how the forebrain and pituitary gland become functionally patterned, and to investigate how axons navigate through the developing brain. Accessible and rapid early development, in combination with the ability to transplant cells between embryos, express genes both transiently and transgenically, and do genetic screens, makes zebrafish a powerful model system for the study for early neural development.

We are characterizing several mutations that disrupt forebrain and pituitary patterning thus disrupt the ability of retinal axons to grow across the forebrain. Using a synteny cloning approach, we have identified the genes affected by the mutations you-too (yot) and detour (dtr). Both loci encode members of the Gli family of transcription factors, proteins that are targets of early differentiation signals mediated by the secreted morphogen sonic hedgehog. We also showed that belladonna (bel), a mutation with similar but subtler axon and forebrain phenotypes, encodes the transcription factor Lhx2.  These mutations disrupt cell differentiation in the ventral forebrain, including the pituitary. One focus of the lab is to understand how Hh/Gli signaling induces and patterns the pituitary gland.  We are also investigating the cellular cues disrupted in the yot, dtr, bel, and umleitung (uml) mutants to better understand how axons are normally guided across the forebrain.  We ultimately hope to understand how cell-cell signaling directs the functional differentiation of midline cells at the anterior end of the developing CNS, as well as to understand the cues that guide axons through their journey from eye to tectum.

Finally, the lab has developed a series of experimental tools that allow us to examine Hh/Gli signaling in post-embryonic development and growth. We are using these tools to understand how Hh/Gli signaling continues to regulate multiple cellular behaviors [differentiation, proliferation, survival] in larval and adult zebrafish tissues.  Since mis-regulation of Hh/Gli signaling can lead to tumorogenesis in humans (bcc, gliomas, adenomas), these studies in zebrafish promise to help us understand the molecular and cellular mechanisms underlying these devastating diseases.

Representative publications:

Guner B, Ozacar AT, Thomas JE, Karlstrom RO. (2008) Graded Hh and Fgf signaling independently regulate pituitary cell fates and help establish the PD and PI of the zebrafish adenohypophysis. Endocrinology. 2008 May 22. [Epub ahead of print]

Bergeron SA, Milla LA, Villegas R, Shen MC, Burgess SM, Allende ML, Karlstrom RO, Palma V. (2008) Expression profiling identifies novel Hh/Gli-regulated genes in developing zebrafish embryos. Genomics. 91(2):165-77

Guner B, Karlstrom RO. (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 Gene Expr Patterns. 2007 Apr 7(5):596-605

Cerda, G.A., Thomas, J.E., Allende, M.A., Karlstrom, R.O. , Palma, V. (in press). Electroporation of DNA, RNA, and morpholinos into zebrafish embryos. Methods .

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.

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 divergent requirements for gli genes in vertebrate
development. Development. 130, 1549-1564

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., J. B. Moss, J. L. Sbrogna, R. O. Karlstrom and L. G. Moss (2002). "Sonic hedgehog is required early in pancreatic islet development." Dev Biol 244(1): 75-84.

Kondoh, H., Ukhikawa, M., Yoda, H., Takeda, 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. 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.