[ Research Interests ] [ Representative Publications ]

Marnie Halpern Adjunct Professor Department of Biology Staff Member Carnegie Institution of Washington B.S. McMaster University M.S. McMaster University Ph.D. Yale University

Carnegie Institution of Washington 3520 San Martin Dr. Baltimore, MD 21218 U.S.A. Office Telephone: Lab Telephone: Department Fax: Email: 410.246.30018 410.246.3029 410.243.6311 halpern@ciwemb.edu Carnegie Institution of Washington

Research Interests Genetic approaches in the zebrafish, Danio rerio enable us to explore how regional specializations arise in the developing neural tube. The zebrafish is ideal for these studies because of its short generation time and ability to produce large numbers of progeny. Eggs are fertilized externally and the resultant embryos develop rapidly and are optically clear, allowing direct visualization of neural development and rapid identification of mutant phenotypes. In vertebrate embryos, evidence suggests that the notochord, a derivative of axial mesoderm, influences differentiation of the overlying neurectoderm. In particular, notochord is thought to be important for induction of the floor plate, the specialized cells at the ventral midline of the neural tube. Floor plate cells in turn provide essential signals for axon guidance at the spinal cord midline and for differentiation of motoneurons. A member of the Hedgehog family of proteins, Sonic hedgehog (SHH), is thought to be the candidate-inducing signal for floor plate and motoneurons. Surprisingly, zebrafish mutants that lack notochords exhibit relatively normal neural development, including differentiation of floor plate and motoneurons. We carried out a detailed analysis of shh expression at gastrulation in relation to expression of tiggy-winkle hedgehog (twhh), another zebrafish hh gene. Cells in the newly forming embryonic axis sort out into discrete hedgehog-expressing layers: shh is expressed by the deep axial mesoderm which gives rise to notochord, whereas twhh is expressed in overlying cells that gives rise to floor plate. Thus, specification of floor plate appears to commence at gastrulation, prior to notochord differentiation. Using gene inactivation methods, we have further shown that HH activity is not essential for floor plate formation in zebrafish. Another signaling pathway has been implicated in floor plate development from the genetic identification of zebrafish cyclops (cyc). Mutant cyclops embryos lack the ventral brain and floor plate. In collaboration with Chris Wright and coworkers (Vanderbilt University), we determined that cyc encodes a nodal-related member of the TGF beta family of signaling peptides. Injection of cyc RNA rescues the ventral brain and floor plate of cyc mutants. Coinjection of tracer RNAs reveals that cyc overexpression in either the ventral neural tube or notochord is insufficient for rescue. However, recovery of the ventral brain and floor plate correlates with the presence of tracer gene activity in derivatives of the prechordal plate, which itself comes from the early gastrula organizer. We propose that it is within this organizer region that patterning of the ventral neural tube occurs, and in agreement, cyc is normally expressed in these cells. We are continuing our studies on the timing and mechanisms that pattern the zebrafish floor plate through overexpression and cell transplantation studies. Curiously, the nodal signaling pathway is also activated transiently on the left side of the zebrafish forebrain, in the epithalamic region. We have to begun to examine how this molecular left-right asymmetry is regulated and its functional significance. Other projects in the lab involve studies of the genetic regulation of myelination and of forebrain morphogenesis. Representative Publications Fisher S, Jagadeeswaran P, Halpern ME. Radiographic analysis of zebrafish skeletal defects. Dev Biol. 2003 264:64-76. Farber SA, De Rose RA, Olson ES, Halpern ME. The zebrafish annexin gene family. Genome Res. 2003 13:1082-96. Halpern ME, Liang JO, Gamse JT. Leaning to the left: laterality in the zebrafish forebrain. Trends Neurosci. 2003 26:308-13. Review. Gamse JT, Thisse C, Thisse B, Halpern ME. The parapineal mediates left-right asymmetry in the zebrafish diencephalon. Development. 2003 130:1059-68. Wright CV, Halpern ME. Specification of left-right asymmetry. Results Probl Cell Differ. 2002 40:96-116. Review. Wright CV, Halpern ME. Specification of left-right asymmetry. Results Probl Cell Differ. 2002 40:96-116. Review. Brosamle C, Halpern ME. Characterization of myelination in the developing zebrafish. Glia. 2002 39:47-57. Gamse JT, Shen YC, Thisse C, Thisse B, Raymond PA, Halpern ME, Liang JO. Otx5 regulates genes that show circadian expression in the zebrafish pineal complex. Nat Genet. 2002 30:117-21. Etheridge LA, Wu T, Liang JO, Ekker SC, Halpern ME. Floor plate develops upon depletion of tiggy-winkle and sonic hedgehog. Genesis. 2001 30:164-9.

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