Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1994-09-19
2001-07-31
Ulm, John (Department: 1812)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C530S300000, C435S069100, C435S069700, C536S023400, C536S023500
Reexamination Certificate
active
06268476
ABSTRACT:
BACKGROUND OF THE INVENTION
Pattern formation is the activity by which embryonic cells form ordered spatial arrangements of differentiated tissues. The physical complexity of higher organisms arises during embryogenesis through the interplay of cell-intrinisic lineage and cell-extrinsic signaling. Inductive interactions are essential to embryonic patterning in vertebrate development from the earliest establishment of the body plan, to the patterning of the organ systems, to the generation of diversive cell types during tissue differentiation (Davidson, E., (1990)
Development
108: 365-389; Gurdon, J. B., (1992)
Cell
68: 185-199; Jessell, T. M. et al., (1992)
Cell
68: 257-270). The effects of developmental cell interactions are varied. Typically, responding cells are diverted from one route of cell differentiation to another by inducing cells that differ from both the uninduced and induced states of the responding cells (inductions). Sometimes cells induce their neighbors to differentiate like themselves (homoiogenetic induction); in other cases a cell inhibits its neighbors from differentiating like itself. Cell interactions in early development may be sequential, such that an initial induction between two cell types leads to a progressive amplification of diversity. Moreover, inductive interactions occur not only in embryos, but in adult cells as well, and can act to establish and maintain morphogenetic patterns as well as induce differentiation (J. B. Gurdon (1992)
Cell
68:185-199).
Many types of communication take place among animal cells during embryogenesis, as well as in the maintenance of tissue in adult animals. These vary from long-range effects, such as those of rather stable hormones circulating in the blood and acting on any cells in the body that possess the appropriate receptors, however distant they are, to the fleeting effects of very unstable neurotransmitters operating over distances of only a few microns. Of particular importance in development is the class of cell interactions referred to above as embryonic induction; this includes influences operating between adjacent cells or in some cases over greater than 10 cell diameters (Saxen et al. (1989)
Int J Dev Biol
33:21-48; and Gurdon et al. (1987)
Development
99:285-306). Embryonic induction is defined as in interaction between one (inducing) and another (responding) tissue or cell, as a result of which the responding cells undergo a change in the direction of differentiation. This interaction is often considered one of the most important mechanismn in vertebrate development leading to differences between cells and to the organization of cells into tissues and organs.
Receptor tyrosine kinases are apparently involved in many different process including cellular differentiation, proliferation, embryonic development and, in some cases, neoplastic growth. High affinity binding of specfic soluble or matrix-associated growth factor ligands can cause the activated receptor to associate with a specific repertoire of cytoplasmic singnalling molecules that can lead to a cascade of intracellular signalling resulting in. for example, activation or inactivation of cellular gene programs involved in differentiation and/or growth. Accordingly, peptide growth factors that are ligands for such receptor tyrosine kinases are excellent candidates for intercellular signaling molecules with important developmental roles. Indeed, these ligands are known to have potent effects on a wide variety of cell activities in vitro. including survival. proliferation, differentiation, adhesion, migration and axon guidance. The powerful signaling effects of these molecules are further emphasized by the ability of both the ligands and the receptors, when activated by mutation or overexpression, to become potent oncogenes and cause drastic cellular transformation (reviewed by Cantley et al. (1991)
Cell
64:281-302; Schlessinger and Ullrich (1992)
Neuron
9:383-391; and Fantl et al. (1993)
Annu Rev Biochem
62:453-481).
To illustrate, specific developmental roles have been demonstrated for some girowth factors or their tyrosine kinase receptors. For example, the c-kit receptor tyrosinie kinase, encoded at the mouse W locus (Chabot et al. (1988)
Nature
335:88-89; and Geissler et al. (1988)
Cell
55:185-192) and its ligand KL, encoded at the mouse Sl locus (Flanagan and Leder (1990)
Cell
63:185-194; Copeland et al. (1990)
Cell
63:175-183; Huang et al. (1990)
Cell
63:225-233; and Zsebo et al. (1990)
Cell
63:213-224), determine the proliferation, survival, and/or migration of primordial germ cells, hematopoietic stem cells, and neural crest progenitor cells. Other examples are the trk family ligands and receptors, with highly specific functions in the developing mammalian nervous system (Klein et al. (1993)
Cell
75:113-122; and Jones et al. (1994)
Cell
76:989-999) and the FGF receptor, implicated in Xenopus mesoderm induction (Amaya et al. (1991)
Cell
66:257-270). In invertebrates, too, receptor tyrosine kinases and ligands such as sevenless, boss, torso, breathless and let-23 are known to play key roles in processes that range from setting up the primary embryonic axes to specifying the fate of a single cell in the ommatidium (Greenwald and Rubin (1992)
Cell
68:271-281; Shilo (1992)
Faseb J
6:2915-2922; and Zipursky et al. (1992)
Cold Spring Horbor Synip Qtuani Biol
57:381-389). Taken together, the emerging picture of the developmental functions of receptor tyrosine kinases and their ligands is striking in that these molecules play key roles at all stages of embryonic development and in a remarkable range of different types of patterning process.
The receptor tyrosine kinases can be divided into families based on structural homology and. in at least some cases, obvious shared functional characteristics (Fantl et al. (1993)
Annu Rev Biochem
62:453-481). The family with by far the largest number of known members is the EPH family. Since the description of the prototype, the EPH receptor (Hirai et al. (1987)
Science
238:1717-1720), sequences have been reported for at least ten members of this family, not counting apparently ortholooous receptors found in more than one species. Additional partial sequences, and the rate at which new members are still being reported, suggest the family is even larger (Maisonpierre et al. (1993)
Oncogene
8:3277-3288; Andres et al. (1 994)
Oncogene
9:1461-1467; Henkemeyer et al. (1994)
Oncogene
9:1001-1014; Ruiz et al. (1994)
Mech Dev
46:87-100; Xu et al. (1994)
Development
120:287-299; Zhou et al. (1994)
J. Neurosci Res
37:129-143; and references in Tuzi and Gullick (1994)
Br J Cancer
69:417-421). Remarkably, despite the large number of members in the EPH family, all of these molecules were identified as orphan receptors without known ligands.
SUMMARY OF THE INVENTION
The present invention relates to the discovery of a novel EPH receptor ligand, referred to hereinafter as “Elf-1”, which protein has apparently broad involvement in the formation and maintenance of ordered spatial arrangements of differentiated tissues in vertebrates, and can be used to generate and/or maintain an array of different vertebrate tissue both in vitro and in vivo.
In general, the invention features an Elf-1 polypeptide, preferably a substantially pure preparation of an Elf-1 polypeptide, or a recombinant Elf-1 polypeptide. In preferred embodiments the polypeptide has a biological activity associated with its binding to an EPH receptor, e.g., it retains the ability to bind to a hek-rclated or sek-related receptor, though it may be able to either agnoize or antagonize signal transduction by the EPH receptor. The polypeptide can be identical to the polypeptide shown in SEQ ID No: 2, or it can merely be homologous to that sequence. For instance, the polypeptide preferably has an amino acid sequence at least 60% homologous to the amino acid sequence in SEQ ID No: 2, though higher sequence homologies of, for example, 80%, 90% or 95% are also contemplated. The polypeptide can comprise the full le
Cheng Hwai-Jong
Flanagan John G.
DeConti, Jr. Giulio A.
Lahive & Cockfield LLP
President and Fellows of Harvard College
Sorensen Kenneth A.
Ulm John
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