How does the genome encode instructions that guide embryonic development?  Our research uses genes that are expressed during vertebrate development as systems for investigating this question.  We have two long-term goals.  The first is to shed light on regulatory events driving bone and cartilage development.  This is relevant to understanding birth defects, osteoporosis and arthritis.  The second is to locate and understand the function of long-range genomic sequences that control gene regulation.  These sequences can act across hundreds of kilobases and are often well conserved.  We study these elements using tools such as BAC (Bacterial Artificial Chromosome) transgenesis and genomic sequence comparisons.

Currently, we are studying three BMP (Bone Morphogenetic Protein) family genes.  All are transcribed in complex patterns during development. Precise regulation of these genes is controlled by multiple, distant cis-regulatory elements.  Using transgenic assays in mice and zebrafish, we are charting out the location of many cis-regulatory elements that are spread across hundreds of kilobases around these genes.  These genes are: Gdf6, which is required for patterning a subset of limb, skull and other skeletal joints during embryonic development; and Bmp2 and Bmp4, both of which are important in bone formation and many sites of organogenesis. Interestingly, each gene is flanked by large “gene deserts” that contain strongly conserved noncoding sequences, some of which are long-distant regulatory elements.  These projects are relevant to understanding the role of noncoding sequences in development and for evolution of skeletal morphology.

Ongoing projects include: (1) Transgenic survey of regulatory function of the mouse Gdf6 3’ “gene desert” which may contain cis-regulatory elements for Gdf6 function in ear, skull, limb or spine joints. (2) Identifying cis-elements of the zebrafish Gdf6a (Radar) gene, using Tol2 transoposon and BAC transgenesis in fish, which will allow evolutionary comparisons to mammalian Gdf6. (3) Identifying function(s) of distant, mammal/fish conserved noncoding elements for the Bmp4 gene, which is crucial for many aspects of organogenesis and mesoderm patterning. (4) Dissecting the molecular mechanisms of a conserved osteoblast cis-enhancer for the Bmp2 gene.  This element lies 156 kb 3’ to Bmp2 and is required for its expression in bone-forming cells, which may be critical for its crucial role as a signaling factor in osteoblast differentiation.  We will dissect the factors that bind this sequence by mutagenesis, gel-shift, chromatin immunoprecipitation and other methods.

Publications

Featured publications

  1. Calcific aortic valve disease: a consensus summary from the Alliance of Investigators on Calcific Aortic Valve Disease. Yutzey KE, Demer LL, Body SC, Huggins GS, Towler DA, Giachelli CM, Hofmann-Bowman MA, Mortlock DP, Rogers MB, Sadeghi MM, Aikawa E (2014) Arterioscler Thromb Vasc Biol 34(11): 2387-93
    › Primary publication · 25189570 (PubMed) · PMC4199903 (PubMed Central)
  2. Dynamics and cellular localization of Bmp2, Bmp4, and Noggin transcription in the postnatal mouse skeleton. Pregizer SK, Mortlock DP (2015) J Bone Miner Res 30(1): 64-70
    › Primary publication · 25043193 (PubMed) · PMC4818007 (PubMed Central)
  3. Recurrent tissue-specific mtDNA mutations are common in humans. Samuels DC, Li C, Li B, Song Z, Torstenson E, Boyd Clay H, Rokas A, Thornton-Wells TA, Moore JH, Hughes TM, Hoffman RD, Haines JL, Murdock DG, Mortlock DP, Williams SM (2013) PLoS Genet 9(11): e1003929
    › Primary publication · 24244193 (PubMed) · PMC3820769 (PubMed Central)
  4. Hox11 genes are required for regional patterning and integration of muscle, tendon and bone. Swinehart IT, Schlientz AJ, Quintanilla CA, Mortlock DP, Wellik DM (2013) Development 140(22): 4574-82
    › Primary publication · 24154528 (PubMed) · PMC3817943 (PubMed Central)
  5. Skeletal trauma generates systemic BMP2 activation that is temporally related to the mobilization of CD73+ cells. Marsell R, Steen B, Bais MV, Mortlock DP, Einhorn TA, Gerstenfeld LC (2014) J Orthop Res 32(1): 17-23
    › Primary publication · 24018651 (PubMed) · PMC4263190 (PubMed Central)
  6. Acute BMP2 upregulation following induction of ischemic osteonecrosis in immature femoral head. Kamiya N, Shafer S, Oxendine I, Mortlock DP, Chandler RL, Oxburgh L, Kim HK (2013) Bone 53(1): 239-47
    › Primary publication · 23219944 (PubMed)
  7. The BMP ligand Gdf6 prevents differentiation of coronal suture mesenchyme in early cranial development. Clendenning DE, Mortlock DP (2012) PLoS One 7(5): e36789
    › Primary publication · 22693558 (PubMed) · PMC3365063 (PubMed Central)
  8. UG4 enhancer-driven GATA-2 and bone morphogenetic protein 4 complementation remedies the CAKUT phenotype in Gata2 hypomorphic mutant mice. Ainoya K, Moriguchi T, Ohmori S, Souma T, Takai J, Morita M, Chandler KJ, Mortlock DP, Shimizu R, Engel JD, Lim KC, Yamamoto M (2012) Mol Cell Biol 32(12): 2312-22
    › Primary publication · 22493062 (PubMed) · PMC3372261 (PubMed Central)
  9. Vascular tissues are a primary source of BMP2 expression during bone formation induced by distraction osteogenesis. Matsubara H, Hogan DE, Morgan EF, Mortlock DP, Einhorn TA, Gerstenfeld LC (2012) Bone 51(1): 168-80
    › Primary publication · 22391215 (PubMed) · PMC3719967 (PubMed Central)
  10. Identifying functional annotation for noncoding genomic sequences. Mortlock DP, Pregizer S (2012) Curr Protoc Hum Genet : Unit1.10
    › Primary publication · 22241655 (PubMed)

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Contact Information

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Keywords & MeSH Terms

MeSH terms are retrieved from PubMed records. Learn more.

Key: MeSH Term Keyword

5'-Nucleotidase Alanine BAC transgenes Base Sequence Bmp2 Bmp4 Body Patterning bone development Cardiac Surgical Procedures Cartilage Chromosome Deletion Connective Tissue developmental biology enhancers Exons Frontal Bone Gdf6 Gene Expression genomics Heart Defects, Congenital human Infant joint development long-range gene regulation mouse genetics Peptides RNA Interference RNA Polymerase II SOXE Transcription Factors Stromal Cells Syndrome transcription factors Transgenes zebrafish genetics