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Olsen Lab

Location: Harvard School of Dental Medicine, Department of Developmental Biology, 188 Longwood Avenue, REB 409, Boston, MA 02115

Summary:

Probing skeletal diseases. Human beings are 60% water; so what keeps us from slipping off our bones and into a puddle on the floor? The short answer is collagen, a chainlike molecule that helps prevent joints from pulling apart and teeth from getting loose. Breakdowns in the formation and organization of collagen cause a number of diseases, including osteoarthritis. The Olsen lab is trying to identify and sequence the genes that help to create different types of collagen. Mice that are missing the gene for one type, collagen IX, seem predisposed to suffer from a disease much like human osteoarthritis. This exciting indication of a genetic cause of arthritis, which the lab is investigating further, creates an even stronger motivation to learn the genetic basis for diseases involving other types of collagen and other proteins in the extracellular matrix that surrounds and connects cells. In addition, the lab is identifying gene mutations that are responsible for defects in skeletal patterns in developing limbs and growth of bones during development. In a recent discovery the inherited disorder synpolydactyly, a condition characterized by extra fingers and variable fusion of fingers, was found to be caused by mutations in a gene, HOXD13, that controls the activity of many other genes which are important for cell growth and differentiation during limb development. Cleidocranial dysplasia, a condition characterized by delayed suture ossification in the skull, supernumerary teeth and missing clavicles, was found to be caused by mutations in the gene CBFA1, a transcription factor needed for cells to become bone cells.


Probing vascular disorders. Blood vessels are tubes of endothelial cells surrounded by layers of smooth muscle cells and connective tissue proteins. During development this complex structure forms as a result of biochemical signals between endothelial cells and smooth muscle cells. Sometimes this biochemical communication fails and abnormal blood vessels form. By analyzing gene mutations causing such vascular abnormalities, much can be learned about the signals that are necessary for normal blood vessel development. In addition, identification of genes responsible for inherited vascular malformations provides a basis for development of rational therapies in the clinical treatment of vascular disorders. One by one, the Olsen lab is trying to identify the genes that cause several forms of venous malformations and determine the precise mutations in these genes.

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Organisms and Viruses

  • C57BL/6J mice ( Mus musculus )

    "C57BL/6J is the most widely used inbred strain and the first to have its genome sequenced. Although this strain is refractory to many tumors, it is a permissive background for maximal expression of most mutations. C57BL/6J mice are resistant to audiogenic seizures, have a relatively low bone density, and develop age related hearing loss. They are also susceptible to diet-induced obesity, type 2 diabetes, and atherosclerosis. Macrophages from this strain are resistant to the effects of anthrax lethal toxin. "

  • Col2a1-Cre;ER*Pkd1 mice ( Mus musculus )

    "A Col2a1 promoter-intron1 enhancer that drives transgene expression in the chondrogenic lineage and notochord was used to express a tamoxifen-responsive Cre transgene in transgenic mice. The promoter driving the transgene contains a fusion gene of Cre and a mutant form of the estrogen receptor (ER*)."

  • Col2a1-CreER*;R26R mice ( Mus musculus )

    "A Col2a1 promoter-intron1 enhancer that drives transgene expression in the chondrogenic lineage and notochord was used to express a tamoxifen-responsive Cre transgene in transgenic mice. The promoter driving the transgene contains a fusion gene of Cre and a mutant form of the estrogen receptor (ER*)."

  • col2α1-Cre ER* transgenic mice ( Mus musculus )

    "A Col2a1 promoter-intron1 enhancer that drives transgene expression in the chondrogenic lineage and notochord was used to express a tamoxifen-responsive Cre transgene in transgenic mice. The promoter driving the transgene contains a fusion gene of Cre and a mutant form of the estrogen receptor (ER*)."

  • Col8a1−/Col8a2− mice ( Mus musculus )

  • Col9a1-/- mice ( Mus musculus )

    Col9a1−/− mice are deficient in type IX collagen

  • DBA/1J mice ( Mus musculus )

    "DBA/1J mice are widely used as a model for rheumatoid arthritis: immunization with type II collagen leads to the development of severe polyarthritis mediated by an autoimmune response. DBA/1J mice show an intermediate susceptibility to developing atherosclerotic aortic lesions on an atherogenic diet. In response to challenge, DBA/1J mice develop immune-mediated nephritis characterized by proteinuria, glomerulonephritis and tubulointerstitial disease."

  • DBA/2J mice ( Mus musculus )

    "DBA/2J is a widely used inbred strain. Some characteristics include low susceptibility to developing atherosclerotic aortic lesions, high-frequency hearing loss, susceptibility to audiogenic seizures, development of progressive eye abnormalities that closely mimic human hereditary glaucoma, and extreme intolerance to alcohol and morphine. "

  • Floxed caALK2 transgenic mice ( Mus musculus )

    "Floxed caALK2 transgenic mice were a gift from Dr. Yuji Mishina (University of Michigan). To induce expression of caALK2, AV-Cre (University of Pennsylvania Vector Core; 1 × 1011 particles per mouse) was injected into the left hindlimbs of mice at one month of age. The contralateral limb was injected with empty vector as a control. Heterotopic bone and cartilage were detected by X-ray (Senographe DS technology, General Electric Medical Systems) at 14-21 d following A V-Cre injection."

  • IRG reporter mice ( Mus musculus )

    "Tie2-Cre and IRG reporter mice were obtained from the Jackson Laboratory. Heterotopic ossification was induced in the offspring of crosses between the Tie2-Cre and IRG reporter mice with BMP4 (provided by Genetics Institute; currently Pfizer) injected at a concentration of 0.05 μg μl−1, intramuscularly in growth factor-reduced Matrigel (BD Biosciences) Tissues were recovered at 7 and 14 d after implantation."

  • Osx1-GFP::Cre mice ( Mus musculus )

    "The Osx1-GFP::Cre mouse line was generated by pronuclear injection of a bacterial artificial chromosome (BAC) containing the Osx1 gene targeted at exon 1, using standard BAC recombination methods"

  • OsxCre;R26R mice ( Mus musculus )

    "To visualize the Cre efficiency, we crossed Wnt1Cre, OsxCre and Col2a1-CreER* mice with the conditional LacZ reporter mouse strain Rosa 26R, in which β-galactosidase expression is activated upon Cre activation. Wnt1Cre;R26R and OsxCre;R26R mice were euthanized at postnatal day 2 and the maxillae including the midpalatal suture were dissected out."

  • SH3BP2 (P416R) mutant mice ( Mus musculus )

    "To obtain insights into SH3BP2 function, we introduced the most common mutation found in cherubism, a proline-to-arginine substitution (P418R in humans; P416R in
    mice), into the mouse Sh3bp2 gene. Mutant mice are osteoporotic with increased numbers of osteoclasts in bone. In addition, homozygotes have massive infiltration of macrophages into skeletal elements and internal organs"

  • Tie2-Cre reporter mice ( Mus musculus )

    "Tie2-Cre and IRG reporter mice were obtained from the Jackson Laboratory. Heterotopic ossification was induced in the offspring of crosses between the Tie2-Cre and IRG reporter mice with BMP4 (provided by Genetics Institute; currently Pfizer) injected at a concentration of 0.05 μg μl−1, intramuscularly in growth factor-reduced Matrigel (BD Biosciences)."

  • Vegfa/loxP mice ( Mus musculus )

  • Wnt1Cre;Pkd1 mice ( Mus musculus )

  • Wnt1Cre;R26R mice ( Mus musculus )

    "To visualize the Cre efficiency, we crossed Wnt1Cre, OsxCre and Col2a1-CreER* mice with the conditional LacZ reporter mouse strain Rosa 26R, in which β-galactosidase expression is activated upon Cre activation. Wnt1Cre;R26R and OsxCre;R26R mice were euthanized at postnatal day 2 and the maxillae including the midpalatal suture were dissected out."


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Last updated: 2013-05-16T07:19:04.361-05:00

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