The Eph subfamily represents the largest branch of membrane-spanning tyrosine kinases known to date. Because it has been identified only recently, it has not yet been extensively characterized. The broad long term objectives of this proposal are to elucidate the functions of the Eph subfamily of tyrosine kinases during retinal morphogenesis and in the mature retina. These studies will suggest possible implications of the Eph-related kinases in the etiology of pathological conditions affecting the retina. The retina also represents a convenient model system to elucidate the roles of the Eph-related kinases in the central nervous system. Different Eph-related kinases have distinct tissue distributions in the adult and, thus, presumably have distinct functions. At least six of the Eph-related kinases that we have identified, namely Cek4, Cek5, Cek6, Cek8, Cek9 and Cek10, are expressed in the developing and adult retina suggesting an important role for the Eph subfamily in the retina. The catalytic activity of the Eph-related kinases is likely to be responsible, at least in part, for the elevated protein tyrosine phosphorylation that is observed both in the developing and mature retina. Cek5, for example, is highly expressed and catalytically active during the differentiation of the retina. This suggests that Cek5 plays an active role during retinal morphogenesis and that mutations of the Cek5 gene are likely to disrupt the normal development of the retina. In addition, the gradient-like distribution of Cek5 in the retina and optic nerve indicates that Cek5 may be involved in the determination of the positional identity and synaptic specificity of retinal ganglion cells. Similarly, the elevated expression of Cek8 throughout the developing optic nerve suggests a role in axonal growth and guidance. To gather information about their possible functions, the spectrum of Eph-related kinases that are expressed in the retina will be identified and their expression levels, spatial distribution and extent of activation in the developing and mature retina will be characterized. The expression and activity of specific Cek Eph- related kinases will be perturbed with antibodies, dominant negative forms, anti sense sequences and ligands. These studies will be performed in vivo and in vitro to address directly the functions of the Eph subfamily in the retina. The identification of the cellular processes that are regulated by the Eph-related kinases, which may include cell fate determination, cell proliferation and differentiation, nerve cell survival and regeneration, cell adhesion and axonal guidance, will allow the manipulation of such processes with possible therapeutic outcomes.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010576-03
Application #
2415027
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1995-05-01
Project End
1999-08-31
Budget Start
1997-05-01
Budget End
1999-08-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
009214214
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Kalo, M S; Yu, H H; Pasquale, E B (2001) In vivo tyrosine phosphorylation sites of activated ephrin-B1 and ephB2 from neural tissue. J Biol Chem 276:38940-8
Menzel, P; Valencia, F; Godement, P et al. (2001) Ephrin-A6, a new ligand for EphA receptors in the developing visual system. Dev Biol 230:74-88
Eberhart, J; Swartz, M; Koblar, S A et al. (2000) Expression of EphA4, ephrin-A2 and ephrin-A5 during axon outgrowth to the hindlimb indicates potential roles in pathfinding. Dev Neurosci 22:237-50
Connor, R J; Menzel, P; Pasquale, E B (1998) Expression and tyrosine phosphorylation of Eph receptors suggest multiple mechanisms in patterning of the visual system. Dev Biol 193:21-35
Pasquale, E B (1997) The Eph family of receptors. Curr Opin Cell Biol 9:608-15
Zisch, A H; Stallcup, W B; Chong, L D et al. (1997) Tyrosine phosphorylation of L1 family adhesion molecules: implication of the Eph kinase Cek5. J Neurosci Res 47:655-65
Holash, J A; Soans, C; Chong, L D et al. (1997) Reciprocal expression of the Eph receptor Cek5 and its ligand(s) in the early retina. Dev Biol 182:256-69
Zisch, A H; Pasquale, E B (1997) The Eph family: a multitude of receptors that mediate cell recognition signals. Cell Tissue Res 290:217-26

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