Non-human animals having a humanized a proliferation-inducing ligand gene

Abstract

Non-human animals, cells, methods and compositions for making and using the same are provided, wherein the non-human animals and cells comprise a humanized a proliferation-inducing ligand gene. Non-human animals and cells that express a human or humanized a proliferation-inducing ligand protein from an endogenous a proliferation-inducing ligand locus are described.

1 . A non-human animal expressing an April polypeptide comprising the extracellular portion of a human APRIL protein linked to the intracellular portion of a non-human animal April protein. 
     
     
         2 . The non-human animal of  claim 1 , wherein the extracellular portion of the human APRIL protein is encoded by exons 2 to 6 of a human APRIL gene. 
     
     
         3 - 6 . (canceled) 
     
     
         7 . The non-human animal of  claim 2 , wherein exons 2 to 6 of the human APRIL gene are at least 90% identical with exons 2 to 6 of a human APRIL gene that appears in Table 3. 
     
     
         8 . (canceled) 
     
     
         9 . The non-human animal of  claim 1 , wherein the non-human animal does not detectably express a full-length endogenous April protein. 
     
     
         10 . The non-human animal of  claim 1 , wherein the April polypeptide is expressed from a humanized April gene at an endogenous April locus. 
     
     
         11 . The non-human animal of  claim 10 , wherein the humanized April gene comprises at least one non-human April exon selected from exon 1, or full or partial exon 6, of a non-human April gene. 
     
     
         12 . (canceled) 
     
     
         13 . A non-human animal comprising a humanized April gene that comprises one or more exons of a human APRIL gene operably linked to a APRIL promoter. 
     
     
         14 . The non-human animal of  claim 13 , wherein the APRIL promoter is a non-human animal April promoter. 
     
     
         15 . The non-human animal of  claim 13 , wherein the APRIL promoter is a human APRIL promoter. 
     
     
         16 . The non-human animal of  claim 13 , wherein the humanized April gene comprises exons 2 to 6 of a human APRIL gene. 
     
     
         17 - 20 . (canceled) 
     
     
         21 . The non-human animal of  claim 16 , wherein exons 2 to 6 of the human APRIL gene are at least 90% identical with exons 2 to 6 of a human APRIL gene that appears in Table 3. 
     
     
         22 . (canceled) 
     
     
         23 . The non-human animal of  claim 13 , wherein the humanized April gene comprises at least one non-human April exon selected from exon 1, or full or partial exon 6, of a non-human April gene. 
     
     
         24 - 29 . (canceled) 
     
     
         30 . An isolated cell or tissue of the non-human animal of  claim 13 . 
     
     
         31 - 36 . (canceled) 
     
     
         37 . A method of making a non-human animal that expresses an April protein from an endogenous April locus, wherein the April protein comprises a human sequence, the method comprising the steps of:
 (a) targeting an endogenous April gene at an endogenous April locus in a non-human embryonic stem (ESS cell with a genomic fragment comprising a human nucleotide sequence that encodes a human APRIL protein in whole or in part;   (b) obtaining a modified non-human ES cell comprising a humanized April gene at the endogenous April locus that comprises the human nucleotide sequence of (a); and,   (c) creating a non-human animal using the modified ES cell of (b).   
     
     
         38 . The method of  claim 37 , wherein the human nucleotide sequence comprises exons 2 to 6 of a human APRIL gene. 
     
     
         39 . The method of  claim 37 , wherein the human nucleotide sequence encodes amino acid residues 87 to 250 of a human APRIL protein. 
     
     
         40 . The method of  claim 37 , wherein the non-human animal is a mouse or rat. 
     
     
         41 - 43 . (canceled) 
     
     
         44 . A method of engrafting human cells into a mouse, the method comprising steps of:
 (a) providing a mouse whose genome comprises a humanized April gene that encodes the extracellular portion of a human APRIL protein linked to the intracellular portion of a mouse April protein; and   (b) transplanting one or more human cells into the mouse.   
     
     
         45 . (canceled) 
     
     
         46 . The method of  claim 44 , further comprising a step of:
 (c) assaying engraftment of the one or more human cells in the mouse   wherein the step of assaying comprises comparing the engraftment of the one or more human cells to the engraftment in one or more wild-type mice or in one or more mice whose genome does not comprise a humanized April gene that encodes the extracellular portion of a human APRIL protein linked to the intracellular portion of a mouse April protein.   
     
     
         47 - 48 . (canceled) 
     
     
         49 . The method of  claim 44 , wherein the human cells are hematopoietic stem cells. 
     
     
         50 . The method of  claim 44 , wherein the human cells are transplanted intravenously, intraperitoneally, or subcutaneously. 
     
     
         51 - 52 . (canceled) 
     
     
         53 . The non-human animal of  claim 1 , wherein the non-human animal is a rodent. 
     
     
         54 . The non-human animal of  claim 13 , wherein the non-human animal is a rodent.