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(12) Patent Application Publication (10) Pub. No.: US 2006/0053503 A1 Culiat Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2006/0053503 A1 Culiat Et Al US 20060053503A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0053503 A1 Culiat et al. (43) Pub. Date: Mar. 9, 2006 (54) CRANIAL AND VERTEBRAL DEFECTS Publication Classification ASSOCATED WITH LOSS-OF-FUNCTION OF NELL (51) Int. Cl. A0IK 67/027 (2006.01) (75) Inventors: Cymbeline T. Culiat, Oak Ridge, TN A6IK 38/17 (2006.01) (US); Eugene M. Rinchik, Holmes, NY C07K I4/705 (2006.01) (US) CI2N 5/06 (2006.01) (52) U.S. Cl. ............................ 800/18; 435/354; 530/350; Correspondence Address: 514/12 QUARLES & BRADY 411 EAST WISCONSNAVENUE MILWAUKEE, WI 53202-4497 (US) (57) ABSTRACT (73) Assignee: UT-Battelle, LLC The mouse Nell1 cDNA and amino acid sequences are (21) Appl. No.: 11/192,813 disclosed. Also disclosed is a Nell1 knock-out mouse with (22) Filed: Jul. 29, 2005 Several bone- and cartilage-related defects. On the molecular level, the loss of Nell1 function led to reduced expression of Related U.S. Application Data certain extracellular matrix proteins. The disclosure here provides new tools for Studying bone and cartilage devel (60) Provisional application No. 60/592,552, filed on Jul. opment as well as new drug Screening and treatment Strat 30, 2004. egies for bone- and cartilage-related diseases and conditions. Patent Application Publication Mar. 9, 2006 Sheet 1 of 3 US 2006/0053503 A1 naq. quqn) nuqa) Sign) a C d g-iH I Zdent sp.) -(9.7 i itsd gn. - ... - . | lipT Ipotif yul, nfiv Patent Application Publication Mar. 9, 2006 Sheet 3 of 3 US 2006/0053503 A1 US 2006/0053503 A1 Mar. 9, 2006 CRANIAL AND VERTEBRAL DEFECTS homozygous for the 17R6' allele (from stock 102DSJ) ASSOCATED WITH LOSS-OF-FUNCTION OF showing a very curled position, enlarged head size and a NELL more Spherical head shape, compared to the control litter mate (left). 17R6' mouse fetuses are recovered alive by CROSS-REFERENCE TO RELATED caesarean rescue because they do not Survive delivery APPLICATIONS through the birth canal perhaps due to the physical trauma in 0001. This application claims the benefit of U.S. provi the neck and Spine region brought about by the abnormal sional application 60/592,552, filed on Jul. 30, 2004. Spinal curvature. STATEMENT REGARDING GOVERNMENT 0007 FIG. 1b shows complementation analysis showing LICENSE RIGHTS the mapping of the l7R6 locus into an interval in mouse chromosome 7 (grey box) that is homologous to a segment 0002 The U.S. Government has a paid-up license in this of human chromosome 11p15 (grey box) where the Nell1 invention and the right in limited circumstances to require gene is located. Mouse chromosome 7 is represented by the the patent owner to license others on reasonable terms as line with a filled circle at the left (indicating the centromere) provided for by the terms of contract Nos. DE-AC05 and relative positions of genes and markers are indicated 000R22725 and KP1104010 awarded by U.S. Department of above the line. Five mutant mouse lines carrying deletions Energy. of varying lengths and Surrounding the pink-eyed dilution BACKGROUND OF THE INVENTION gene (p) are shown as 46DFiOD, 47DTD, 2MNURf, 0003) Nell1 is a protein kinase C (PKC) B-binding pro 8R250M and 3R30M. Among these mutations only the tein (Kuroda, S. & Tanizawa, K. Biochem. Biophys. Res. 3R30M deletion can complement the ENU-induced muta Commun. 265, 752-757, 1999, incorporated herein by ref tions at 17R6 indicating that this deletion does not extend to erence in its entirety). The Nell1 cDNA and amino acid the position where the 17R6 gene is located. The interval is Sequences from a variety of mammalian Species are avail therefore defined by the proximal deletion breakpoints of the able. For example, human Nell1 cDNA can be found at 8R250M and 3R3OM mutant mouse lines. GenBank Accession No. BC096102 (SEQ ID NO:3 and the 0008 FIG. 2a shows Nell1 expression profiles in heads corresponding amino acid Sequence is provided as SEQ ID (H) and bodies (B) of wild-type embryos/fetuses (samples NO:4) and rat Nell1 cDNA can be found at GenBank 1-8) and adult mouse tissues (samples 9-16). Samples are as Accession No. NM 031069 (SEQ ID NO:5 and the corre follows: 1, E10; 2, E12;3, E14H; 4, E14 B; 5, E16H; 6, E16 sponding amino acid Sequence is provided as SEQ ID B; 7, E18H; 8, E18 B; 9, brain; 10, liver; 11, spleen; 12, NO:6). The full length mouse Nell1 gene corresponding to kidney; 13, thymus, 14, heart; 15, lung; 16, muscle. The the above human and rat Sequences, however, has not been Nell1 cDNA probe detects a 3.5-kb transcript as early as E10 identified and cloned. days. From E14-E18 days, the Nell1 message is abundant in 0004 Overexpression of Nell1 has been shown to cause both fetal heads and bodies, increasing dramatically in the premature fusion of the growing cranial bone fronts, result head as development proceeds. Hybridization of the blot ing in cranioSynostosis in humans and transgenic mice with an actin probe Serve as control to compare levels of carrying a rat Nell1 transgene (Zhang, X. et al. J. Clin. Samples loaded in each lane. Invest. 110, 861-870, 2002; and Ting, K. et al. J. Bone 0009 FIG.2b shows Northern blot analysis on polyA+ Miner. Res. 14,80-89, 1999). It is not known, however, what RNAS extracted from the heads of hemizygous E1517R6 an effect a loss of NELL1 function will have on mammalian embryos. A Severely reduced expression of the Nell1 gene in animals. In addition, PKC-B has been shown to localize in the 17R6' (102DSJ) allele was observed when compared to the vertebrate bodies and intervertebral disc spaces of normal levels of expression detected in mice with the human fetuses during the 8" week of development, a critical following genotypes: wild-type, mutant hemizygote carry development period when chondrogenetic and Osteogenetic ing an ENU-induced mutation in a gene linked to the p processes are initiated in the vertebral column (Bareggi, R. region (335SJ), and the three original alleles at the 17R6 et al. Boll. Soc. Ital. Biol. Sper. 71, 83-90, 1995). It is locus (88SJ, 435DSJ, 2038SJ). currently not known whether alteration in Nell1 activity will affect Spinal development and Structure. 0010 FIG.3a shows mouse Nell1 cDNA sequence (part of SEQ ID NO:1), the corresponding amino acid sequences BRIEF SUMMARY OF THE INVENTION (SEQ ID NO:2), and protein domains. The location of the 0005 The mouse Nell1 cDNA and amino acid sequences ENU-induced mutation at bp No. 1546 in the cysteine codon are disclosed. Also disclosed is a Nell1 knock-out mouse (amino acid No. 502) are both shown. The premature with Several bone- and cartilage-related defects. On the termination codon introduced at this site will truncate the molecular level, the loss of Nell1 function led to reduced protein and remove the EGF-like domains that are essential expression of certain extracellular matrix proteins. The for the binding to PKC B1. disclosure here provides new tools for Studying bone and 0011 FIG. 3b shows sequence electropherograms and cartilage development as well as new drug Screening and the identification of the 102DSJ mutation. The wild-type treatment Strategies for bone- and cartilage-related diseases Sequence is shown on the left while the mutant Sequence is and conditions. on the right. Arrows indicate the position of the T to Abase BRIEF DESCRIPTION OF THE SEVERAL change. VIEWS OF THE DRAWINGS 0012 FIG. 4a shows skeletal defects in 17R6/Nell1 0006 FIG. 1a shows the phenotype of 17R6 homozy homozygote mutant mouse (right) at 18 days of gestation. gote mutants at 19 days of gestation. On the right is a fetus There is alteration of Spinal curvature, decreased in inter US 2006/0053503 A1 Mar. 9, 2006 vertebral disc Spaces, reduced thoracic Volume, protruding nucleic acid and polypeptide of the invention can be isolated Sternum and a slight enlargement of the skull. and purified from normally associated material in conven tional ways Such that in the purified preparation the nucleic 0013 FIG. 4b is a closeup of the cervical region where acid or polypeptide is the predominant Species in the prepa the most pronounced vertebral compression is located. ration. At the very least, the degree of purification is Such DETAILED DESCRIPTION OF THE that the extraneous material in the preparation does not INVENTION interfere with use of the nucleic acid or polypeptide of the invention in the manner disclosed herein. The nucleic acid or 0.014. The present invention is based on the inventors polypeptide is preferably at least about 85% pure, more cloning and determination of the full length cDNA sequence preferably at least about 95% pure, and most preferably at of the mouse Nell1 gene and the generation of Nell1 least about 99% pure. knock-out mice. The inventors observed that, in comparison 0018 Further, an isolated nucleic acid has a structure that to normal control mice, the Nell1 knock-out mice had is not identical to that of any naturally occurring nucleic acid altered cranial morphology, overgrowth of the parietal and or to that of any fragment of a naturally occurring genomic frontal calvarial bones, altered Spinal curvature, decreased nucleic acid Spanning more than three separate genes. The intervertebral Spaces, reduced thoracic volume, and raised term therefore covers, for example, (a) a DNA that has the ribs. The defects in the vertebral column and rib cage of Sequence of part of a naturally occurring genomic DNA Nell1 knock-out mice indicate that Nell1 plays an important molecule but which is not flanked by both of the coding role in endochondral OSSification.
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