'signalin' family of TGFbeta signal transduction proteins and uses related thereto

Abstract

The present invention concerns the discovery that proteins encoded by a family of vertebrate genes, termed here signalin-related genes, which are involved in a signal transduction induced by members of the TGFβ superfamily. The present invention makes available compositions and methods that can be utilized, for example to generate and/or maintain an array of different vertebrate tissue both in vitro and in vivo.

1 - 71 . (canceled)  
     
     
         72 . A method for modulating one or more of growth, differentiation, or survival of a mammalian cell responsive to signalin-mediated induction, comprising treating the cell with an effective amount of an agent which modulates the signal transduction activity of a signalin polypeptide thereby altering, relative to the cell in the absence of the agent, at least one of (i) rate of growth, (ii) differentiation, or (iii) survival of the cell.  
     
     
         73 . The method of  claim 72 , wherein said agent mimics the effects of a naturally-occurring signalin protein on said cell.  
     
     
         74 . The method of  claim 72 , wherein said agent antagonizes the effects of a naturally-occurring signalin protein on said cell.  
     
     
         75 . The method of  claim 72 , wherein the cell is a testicular cell and the agent modulates spermatogenesis.  
     
     
         76 . The method of  claim 72 , wherein the cell is an osteogenic cell, and the agent modulates osteogenesis.  
     
     
         77 . The method of  claim 72 , wherein the cell is a chondrogenic cell, and the agent modulates chondrogenesis.  
     
     
         78 . The method of  claim 72 , wherein the agent modulates the differentiation of neuronal cells.  
     
     
         79 - 88 . (canceled)  
     
     
         89 . A diagnostic assay for identifying a cell or cells at risk for a disorder characterized by unwanted cell proliferation or differentiation, comprising detecting, in a cell sample, the presence or absence of a genetic lesion characterized by at least one of (i) aberrant modification or mutation of a gene encoding a signalin protein, and (ii) mis-expression of said gene; wherein a wild-type form of said gene encodes a signalin protein characterized by an ability to modulate the signal transduction activity of a TGFβ receptor.  
     
     
         90 . The assay of  claim 89 , wherein detecting said lesion includes: 
 i. providing a diagonistic probe comprising a nucleic acid including a region of nucleotide sequence which hybridizes to a sense or antisense sequence of said gene, or naturally occurring mutants thereof, or 5′ or 3′ flanking sequences aurally associated with said gene;    ii. combining said probe with nucleic acid of said cell sample; and    ii. detecting, by hybridization of said probe to said cellular nucleic acid, the existence of at least one of a deletion of one or more nucleotides from said gene, an addition of one or more nucleotides to said gene, a substitution of one or more nucleotides of said gene, a gross chromosomal rearrangement of all or a potion of said gene, a gross alteration in the level of an mRNA transcript of said gene, or a non-wild type splicing pattern of an mRNA transcript of said gene.    
     
     
         91 . The assay of  claim 90 , wherein hybridization of said probe further comprises subjecting the probe and cellular nucleic acid to a polymerase chain reaction (PCR) and detecting abnormalities in an amplified product.  
     
     
         92 . The assay of  claim 90 , wherein hybridization of said probe further comprises subjecting the probe and cellular nucleic acid to a ligation chain notion (LCR) and detecting abnormalities in an amplified product.  
     
     
         93 . The assay of  claim 90 , wherein said probe hybridizes under stringent conditions to a nucleic acid designated by one or more of SEQ ID Nos. 1-13.  
     
     
         94 . A method for screening for compounds that modulate an activity of a signalin polypeptide, comprising 
 providing a signalin polypeptide and a molecule;    contacting said signalin polypeptide and said molecule with a compound; and    assaying binding of said signalin polypeptide to said molecule in the presence versus the absence of said compound, thereby identifying a compound that modulates the activity of a signalin polypeptide.    
     
     
         95 . The method of  claim 94 , wherein the activity of a signalin polypeptide comprises modulating signaling via the TGFβ signaling pathway.  
     
     
         96 . The method of  claim 95 , wherein the compound is an antagonist that inhibits signaling via the TGFβ signaling pathway.  
     
     
         97 . The method of  claim 95 , wherein the compound is an agonist that promotes signaling via the TGFβ signaling pathway.  
     
     
         98 . The method of  claim 94 , wherein the molecule is a protein.  
     
     
         99 . The method of  claim 94 , wherein the molecule is a nucleic acid.  
     
     
         100 . The method of  claim 94 , wherein the compound promotes binding of the signalin polypeptide to the molecule.  
     
     
         101 . The method of  claim 94 , wherein the compound inhibits binding of the signalin polypeptide to the molecule.  
     
     
         102 . A method for screening for compounds that modulate an activity of a signalin polypeptide, comprising 
 providing a cell that expresses a signalin polypeptide, which cell is responsive to TGFβ signaling;    contacting said cell with a compound; and    assaying signalin inductive responses in the cell in the presence versus the absence of said compound, thereby identifying a compound that modulates the activity of a signalin polypeptide.    
     
     
         103 . The method of  claim 102 , wherein assaying signalin inductive responses in the cell comprises assaying cell proliferation or cell differentiation.  
     
     
         104 . The method of  claim 102 , wherein assaying signalin inductive responses comprises assaying signaling via the TGFβ signaling pathway.  
     
     
         105 . The method of  claim 102 , wherein assaying signalin inductive responses comprises measuring expression of genes which are regulated by the TGFβ signaling pathway.  
     
     
         106 . The method of  claim 102 , wherein the activity of a signalin polypeptide comprises modulating signaling via the TGFβ signaling pathway.  
     
     
         107 . The method of  claim 106 , wherein the compound is an antagonist that inhibits signaling via the TGFβ signaling pathway.  
     
     
         108 . The method of  claim 106 , wherein the compound is an agonist that promotes signaling via the TGFβ signaling pathway.  
     
     
         109 . The method of  claim 102 , wherein the cell expresses a recombinant signalin polypeptide.