Eric S. Weinberg
Professor, Dept of Biology

Developmental Biology Program

Address
204E Lynch Laboratories


Office tel.: 215-898-4198
Lab tel.: 215 898-2640
Fax: 215 898-8780
E-mail: eweinber@sas.upenn.edu

Education

University of Rochester, B.A. (Chemistry),1963

Rockefeller University, Ph.D. (Developmental Biology), 1969

Research Interests

• Our lab is involved in a set of projects on the control of pattern formation and tissue differentiation in the zebrafish embryo, focusing mainly on axis formation and the development of the nervous system and head sensory structures, including the inner ear.

Key words: zebrafish, neural development, brain, ear, sensory ganglia, organizer, beta-catenin.

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Description of Research

Our lab is involved in a set of projects on the control of pattern formation and tissue differentiation in the zebrafish embryo, focusing mainly on axis formation, and the development of the nervous system and head sensory structures, including the inner ear.

1. Roles of the two zebrafish β-catenins in formation of the embryonic organizer
   One of the most fundamental issues in embryonic development is how the anterior-posterior and dorsal-ventral axes are determined. This patterning is controlled in part by a dorsal tissue termed 'the organizer' whose formation is dependent on signaling through the Wnt/β-catenin pathway. The zebrafish has two β-catenin genes, and we have shown that organizer formation is completely dependent on one of these two genes, β-catenin-2. We have characterized a maternal effect mutation (ichabod) that has a chromosomal rearrangement near the β-catenin-2 gene, specifically resulting in a decrease in maternal transcripts from this gene and a consequent failure of embryos to form the dorsal organizing center. Morpholino oligonucleotide knock-down experiments confirm a requirement for β-catenin-2 and not β-catenin-1. The two β-catenin proteins are very similar in sequence (93% identity) and both transcripts are expressed ubiquitously. Using an antibody specific for ?-catenin-1, we have found that this protein is expressed in prospective dorsal organizer cells but is less frequently located in nuclei than is β-catenin-2. The two proteins differ most in the 100 C-terminal amino acids and we are now beginning to study whether the C-termini confer differences in sub-cellular localization, protein stability, and or the ability to interact preferentially with particular binding partners. The control of such processes has importance beyond the study of organizer formation, as the partition of β-catenin between the nucleus and cadherin located in the cell membrane is a key factor in whether the protein acts as an oncogen.
2. Interaction between Nodal and FGF signaling pathways in induction of dorsal mesoderm
   Using wild-type and ichabod mutant embryos, we have worked out the pathway of genes activated by beta-catenin-2 in the organizing center. FGF signaling is essential for organizer formation and this signaling is activated by beta-catenin-2 acting through Nodal signals. FGFs in the organizer are essential for dorsal chordin expression and are also essential for control of stability of transcripts for a key organizer transcription factor, Bozozok. Using transplantation experiments, we have now shown that FGF signaling is required for Nodal induction of chordin, noggin1, goosecoid, and no tail (Brachyury), but not for induction of FGF genes. FGFs might thus be intermediate signaling molecules (relays) under some conditions. We are currently pursuing experiments to distinguish between relays and a requirement for autocrine FGF signaling in responding cells.
3. A screen for inner ear and cranial sensory ganglia mutations
   We are presently carrying out a mutant screen for new inner ear mutants. One group of mutants, in which the ear is smaller and the acoustic ganglion precursors are reduced, is of special interest.
   

Recent Publications

Kozlowski, D.J., Whitfield, T.T., Hukriede, N.A., Gai, W., Lam, W.K. and Weinberg, E.S. (2005). The zebrafish dog-eared mutation disrupts eya1, a gene required for cell survival and differentiation in the inner ear and lateral line. Dev. Biol. 277: 27-41.

Gore, A., Maegawa, S., Gilligan, P., Weinberg, E.S., and Sampath, K. (2005). The zebrafish dorsal axis is specified by the 4-cell stage. Nature 438: 1030-1035.

Bellipanni, G., Varga, M., Maegawa, S., Imai, Y., Kelly, C., Pomrehn, A., Chu, F., Talbot, W.S., and Weinberg, E.S. (2006). Essential and opposing roles of zebrafish β-catenins in formation of dorsal axis structures and development of neurectoderm. Development 133: 1299-1309.

Maegawa, S., Varga, M., and Weinberg, E.S. (2006). FGF signaling is required for β-catenin-mediated induction of the zebrafish organizer. Development 133: 3265-3276.

Varga, M., Maegawa, S., Bellipanni, G., and Weinberg, E.S. (2007). Chordin expression, medieated by Nodal and FGF signaling is restricted by redundant function of two ?-catenins in the zebrafish embryo. Mech. Dev. (in press).

Lab

Rotation Projects

1. Testing the interaction of the zebrafish β-catenins with binding partners: For the rotation project, we will focus on Legless (Lgs) and Pygopus (Pygo). Lgs binds directly to β-catenin and serves as an adapter to recruit Pygo to the complex. Formation of the complex is required for efficient nuclear localization of β-catenin. As there are two Lgs genes, a possibility is that there are preferential interactions of Lgs and β-catenin proteins that may determine which of the two β-catenins is preferentially localized in nuclei. We will test rescue efficiency of the two Lgs RNAs, when coinjected with Pygo RNA. Using wild-type embryos, we will test the effects of expression of each form on nuclear localization of each of the two β-catenins.
2. Control of chordin expression in zebrafish: In Xenopus, Nodal-related proteins activate the chd promoter by a two step indirect process. Xlim1 is activated by Nodal-related factor activation of Smad3. Xlim1 and Smic1 (a zinc finger protein expressed maternally in the Xenopus embryo) then form a complex that can activate the XChordin promoter (Collart et al., 2005b). It is unknown whether this mechanism operates also in zebrafish. Although zebrafish lim1 appears to be under Nodal signaling control, we will test if FGF signaling is required for, and is sufficient for expression of lim1. We will test if lim1 is required (by using MOs for lim1) for FGF non cell-autonomous induction of chd in our transplantation assay and also test whether a zebrafish Smic1 protein is required for chd expression. At least one Smic1 homolog is present in the zebrafish sequence data base and we will design MOs to test for effects of loss of function on chd expression and on embryonic phenotype.
3. Analysis and genetic mapping of zebrafish ear and head sensory structure mutants. The rotation student will genetically map one of our newly identified mutants and will also characterize the defects in the mutant using in situ hybridization. This project will allow a student to learn how to do genetic mapping using simple sequence repeat polymorphic markers and to test for genes that are candidates for the mutated locus.
   
   

Lab personnel:

Gianfranco Bellipanni, Research Fellow
Joshua Bradner, Research Specialist
Jared Rudick, Research Specialist

last updated 7/2007