Faculty: Department of Molecular Genetics: Ohio State University:

Susan Cole

282 Biosciences Building
484 W 12th Avenue
Columbus, OH 43210-1292
Phone: 614-292-3276
Email/web:
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Focus

Roles of fringe genes and Notch signaling during development. Analysis of cyclic mRNA expression during somitogenesis: linking the Notch pathway and the segmentation clock.

Research interests

Our lab is interested in the roles of the Notch signaling pathway during mouse embryonic development. One area of focus is on the roles of fringe genes in Notch pathway modulation. The fringe genes encode glycosyltransferases that modify Notch and its ligands. Mice have three fringe genes: Lunatic fringe (Lfng), Manic fringe (Mfng) and Radical fringe (Rfng).

Lunatic fringe is a critical gene during vertebrate segmentation. The vertebrate body axis consists of serially repeated elements, the most evident of which are the vertebrae of the skeleton. Somites, which are the precursors of the axial skeleton, therefore provide one of the most obvious examples of segmentation in developing vertebrate embryos. The Notch pathway in general, and Lunatic fringe specifically are required for proper regulation of somitogenesis.

It was proposed over 20 years ago that somitogenesis would be regulated by a cellular clock. Recently many gene expression patterns have been linked to this clock, The mRNA levels of these "clock" genes oscillate with a periodicity that matches the timing of somite formation, supporting the existence of a segmentation clock that regulates somitogenesis. Lfng is one of these cyclic genes, providing a direct link between the segmentation clock and Notch signaling. Using mouse genetics techniques, we identified minimal regulatory elements sufficient to drive cyclic expression of Lfng, and identified specific binding sites required for this regulation. By mutating this critical sequence in the endogenous Lfng locus, we recently found that oscillatory Lfng expression is critical only for development of the anterior skeleton, but is dispensable during tail formation. Interestingly, we find that a second, separable Lfng function during somite patterning is critical for tail development. We are actively pursuing the mechanisms by which Notch signaling plays distinct roles during primary body formation (development of the thoracic and lumbar skeleton) and secondary body formation (development of the sacral and tail vertebrae).

In other projects, we are assessing the post-transational mechanisms that regulate Lfng during clock function. We are also using genetic manipulation and breeding to create mice that are deficient for two or all three fringe genes to uncover roles for fringe genes that may be hidden by genetic redundancy.

Laboratory Personnel:

Graduate Students: Emily Shifley, Maurisa Riley
Undergraduate Students: Meaghan Ebetino, Jason Lather, Kristin Ostmann
Research Technician: Dawn Walker

PUBLICATIONS:

Shifley, E.T., VanHorn, K.M., Perez-Balaguer, A., Franklin, J.D., Weinstein, M. and Cole, S.E. (2008) Oscillatory Lunatic fringe activity is critical for segmentation of the anterior but not posterior skeleton. Development 135: 899-908

Shifley, E.T. and Cole, S.E. (2007) The vertebrate segmentation clock and its role in skeletal birth defects. Birth Defects Res C Embryo Today. 81:121-133.

Cole, S.E., J.M. Levorse, S.M. Tilghman, T.F. Vogt. (2002). Clock regulatory elements control cyclic expression of Lunatic fringe during somitogenesis. Dev Cell 3: 75-84.

Bendotti C, S.E. Cole, M. Gobbi, C. Hohmann and R.H. Reeves. (2002) Overexpression of S100ß in transgenic mice does not protect from serotonergic denervation induced by 5,7-dihydroxytryptamine (5,7-dht). J Neurosci Res. 67:501-510.

Cole, S.E., M.S. Mao, S.H. Johnston, T.F. Vogt. (2001) Identification, expression analysis and mapping of B3galt6, a putative galactosyltransferase with similarity to Drosophila brainiac. Mammalian Genome 12:177-179.

Bohne, J., S.E. Cole, C. Sune, B.R. Lindman, V.D. Ko, T.F. Vogt, M.A. Garcia-Blanco. (2000) Expression analysis and mapping of the mouse and human transcriptional regulator CA150. Mammalian Genome 11:930-933.

Wiltshire T., M. Pletcher, S.E. Cole, M. Villanueva, B. Birren, J. Lehoczky, K. Dewar, R.H. Reeves. (1999) Perfect conserved linkage across the entire mouse Chromosome 10 region homologous to human Chromosome 21. Genome Res 9:1214-1222.

Cole, S.E., T. Wiltshire, E.E. Rue, D. Morrow, P. Hieter, C. Brahe, N. Katsanis, E.M. Fisher, R.H. Reeves. (1999) High resolution physical and comparative mapping of mouse Chromosome 10 in a region of conserved synteny with human Chromosome 21. Mammalian Genome 10:229-234.

Cole, S.E., and R.H. Reeves. (1998) A cluster of keratin associated proteins on MMU10 in the region of conserved linkage with HSA 21. Genomics 54:437-442.

Cole, S.E., T. Wiltshire, R.H. Reeves. (1998) Physical mapping of the evolutionary boundary between human Chromosomes 21 and 22 on mouse Chromosome 10. Genomics 50: 109-111.

Mjaatvedt A.E., D.E. Cabin, S.E. Cole, L.J. Long, G.E. Breitwieser, R.H. Reeves. (1995) Assessment of a mutation in the H5 domain of Girk2 as a candidate for the weaver mutation. Genome Res 5:453-463.

Lazebnik Y.A., S. Cole, C.A. Cooke, W.G. Nelson, W.C. Earnshaw. (1993) Nuclear events of apoptosis in vitro in cell-free mitotic extracts: a model system for analysis of the active phase of apoptosis. J Cell Biol 23:7-22.