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(12) Patent Application Publication (10) Pub. No.: US 2003/0106074 A1 Serafini (43) Pub US 2003O106074A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0106074 A1 Serafini (43) Pub. Date: Jun. 5, 2003 (54) COLLECTIONS OF TRANSGENIC ANIMAL Publication Classification LINES (LIVING LIBRARY) (51) Int. Cl." ...................... A01K 67/033; AO1K 67/027 (76) Inventor: Tito Andrew Serafini, San Mateo, CA (52) U.S. Cl. ................................................... 800/8: 800/14 (US) (57) ABSTRACT Correspondence Address: The invention provides collections of transgenic animals and PENNIE AND EDMONDS vectors for producing transgenic animals, which transgenic 1155 AVENUE OF THE AMERICAS animals and vectors have a transgene comprising Sequences NEW YORK, NY 100362711 encoding a detectable or Selectable marker, the expression of which marker is under the control of regulatory Sequences (21) Appl. No.: 10/077,025 from an endogenous gene Such that when the transgene is present in the genome of the transgenic animal, the detect (22) Filed: Feb. 14, 2002 able or Selectable marker has the same expression pattern as the endogenous gene. Such transgenic animals can then be Related U.S. Application Data used to detect, isolate and/or Select pure populations of cells having a particular functional characteristic. The isolated (63) Continuation-in-part of application No. 09/783,487, cells have uses in gene discovery, target identification and filed on Feb. 14, 2001. validation, genomic and proteomic analysis, etc. Patent Application Publication Jun. 5, 2003. Sheet 1 of 13 US 2003/0106074 A1 sixxx; : ?,graecaeaeaeaeae ·:>`()~(ºrº?anaeru: !!¿*(:,!!!!!(!!!!!..”):straes) - k wis **** ************ FIG . 1 A FIG. 1B Patent Application Publication Jun. 5, 2003. Sheet 2 of 13 US 2003/0106074 A1 clone2 *********** ******$$x***** *******. šasº,:*** ********* ***** Six FG.2 Patent Application Publication Jun. 5, 2003. Sheet 3 of 13 US 2003/0106074 A1 col Patent Application Publication Jun. 5, 2003. Sheet 4 of 13 US 2003/0106074 A1 Patent Application Publication Jun. 5, 2003. Sheet 5 of 13 US 2003/0106074 A1 5 Patent Application Publication Jun. 5, 2003. Sheet 6 of 13 US 2003/0106074 A1 O D d5 5, a asO 9 A. E. cud CO2 (f)) O *** - is is is a fix .si i zi sy an . aware ar, owoom i. era as ". saaroops a . Signature Doublet (2.2kb, 1.9kb) Patent Application Publication Jun. 5, 2003. Sheet 7 of 13 US 2003/0106074 A1 D CO i FIG.7 Patent Application Publication Jun. 5, 2003. Sheet 8 of 13 US 2003/0106074 A1 Unmodified Cointegrate ##########~ ***** Patent Application Publication Jun. 5, 2003. Sheet 9 of 13 US 2003/0106074 A1 ?, ************************&&&&!»,«»: FIG.9 Patent Application Publication Jun. 5, 2003. Sheet 10 of 13 US 2003/0106074 A1 stree , & ...'... i. - f : * r * , Patent Application Publication Jun. 5, 2003. Sheet 11 of 13 US 2003/0106074 A1 FIG 11 Patent Application Publication US 2003/0106074 A1 Patent Application Publication Jun. 5, 2003. Sheet 13 of 13 US 2003/0106074 A1 US 2003/0106074 A1 Jun. 5, 2003 COLLECTIONS OF TRANSGENIC ANIMAL LINES which the expression pattern of a gene in a known cell type (LIVING LIBRARY) that potentially encodes a drug target may be monitored. We 0001. The present application is a continuation-in-part of describe Such a technology here. application Ser. No. 09/783,487 filed Feb. 14, 2001, which is incorporated herein by reference in its entirety. 3. SUMMARY OF THE INVENTION 0007. The invention provides lines of transgenic animals, 1. TECHNICAL FIELD preferably mice, in which a Subset of cells characterized by expression of a particular endogenous gene (a “characteriz 0002 The present invention relates to methods for pro ing gene') expresses, either constitutively or conditionally, ducing transgenic animal lines and vectors for producing a “system gene,” which preferably encodes a detectable or Such transgenic animal lines in which a particular Subset of Selectable marker or a protein product that induces or cells, characterized by the expression of a particular endog Suppresses the expression of a detectable or Selectable enous gene, expresses a detectable or Selectable marker or a marker (e.g., the protein product is a transcription factor and protein product that Specifically induces or Suppresses a the expression of the detectable or Selectable marker, or detectable or selectable marker. The invention provides Suppression thereof is dependent upon the transcription collections of Such lines of transgenic animals and vectors factor, for example, the nucleotide Sequence encoding the for producing them, and also provides methods for the detectable or Selectable marker is operatively linked to a detection, isolation and/or Selection of a Subset of cells regulatory element recognized by the System gene product) expressing the marker gene in Such transgenic animal lines. allowing detection, isolation and/or Selection of the Subset of cells from the other cells of the transgenic animal, or 2. BACKGROUND OF THE INVENTION explanted tissue thereof. In a preferred embodiment, the 0003. An important goal in the design and development transgene introduced into the transgenic animal includes at of new therapies for human diseases and disorders is char least the coding region Sequences for the System gene acterizing the responses of afflicted cell types to candidate product operably linked to all or a portion of the regulatory therapeutic molecules. The complexity of tissueS Such as the Sequences from the characterizing gene Such that the System nervous System, however, poses a challenge for those Seek gene has the same pattern of expression within the animal ing to identify new therapeutic molecules based on the (i.e., is expressed Substantially in the same population of responses of a particular identified cell type. The enormous cells) or within the anatomical region containing the cells to heterogeneity of the nervous System (thousands of neuronal be analyzed as the characterizing gene. Also, preferably, the cell types) and of cell-specific patterns of gene expression transgene containing the System gene coding Sequences and (more genes are expressed in the brain than in any other characterizing gene Sequences is present in the genome at a organ or tissue), as well as the Scarcity of relevant cell-based Site other than where the endogenous characterizing gene is assays for high-throughput Screening, are Serious barriers to located. In preferred embodiments, the invention provides the design and development of new therapies. Few cell types Such lines of transgenic animals in which the characterizing can be isolated in a pure population by dissection and gene is one of the genes listed in Tables 1-15, infra. immortalized cell lines derived from a particular cell type 0008. The invention further provides methods of produc are often unavailable or have changed physiologically from ing Such transgenic animals and vectors for producing Such the cell type present in an organism. transgenic animals. In particular, each transgenic line is created by the introduction, for example by pronuclear 0004. A technology that would permit more rapid recog injection, of a vector containing the transgene into a founder nition, identification, characterization and/or isolation of animal, Such that the transgene is transmitted to offspring in pure populations of a particular cell type would, therefore, the line. The transgene preferably randomly integrates into have broad application to numerous types of experimental the genome of the founder but in Specific embodiments may protocols, both in Vivo and in Vitro, for example, pharma be introduced by directed homologous recombination. In a cological, behavioral, physiological, and electrophysiologi preferred embodiment, homologous recombination in bac cal assays, drug discovery assays, target validation assays, teria is used for target-directed insertion of the System gene etc. Sequence into the genomic DNA for all or a portion of the 0005 Aparticular cell type can be classified, interalia, by characterizing gene, including Sufficient characterizing gene the Specific Subset of genes it expresses out of the total regulatory Sequences to promote expression of the charac number of genes in the genome. Identification of a cell type terizing gene in its endogenous expression pattern. In a based on the analysis of its patterns of gene expression preferred embodiment, the characterizing gene Sequences among the cells of an organism can be laborious, however, are on a bacterial artificial chromosome (BAC). In specific in the absence of easily recognized genetic or molecular embodiments, the System gene coding Sequences are markers, Such as markers that are detectable by human eye inserted as a 5" fusion with the characterizing gene coding or by an automated detector or cell Sorting apparatus. Sequence Such that the System gene coding Sequences are 0006 Once a particular cell type is identified among the inserted in frame and directly 3' from the initiation codon for cells of an organism, the genes that impart functionally the characterizing gene coding Sequences. In another relevant properties to that cell type and the responses of the embodiment, the System gene coding Sequences are inserted cells to experimental treatments can be recognized and into the 3' untranslated region (UTR) of the characterizing assayed more easily. The ability to identify and isolate gene and, preferably, have their own internal ribosome entry distinct cell types within an organism Systematically based sequence (IRES). upon the expression of a marker gene driven by an endog
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