Vanderbilt University School of Medicine

Mortlock, Douglas P. , Ph.D.
Research Assistant Professor of Molecular Physiology and Biophysics

Lab Url: N/A

Phone Number: (615) 936-1671


Mortlock, Douglas's picture

Office Address   Mailing Address

1175 Light Hall

519 Light Hall (Center for Human Genetics Research) Vanderbilt University Medical Center 37232-0700

Research Keywords
Long-range gene regulation, genomics, developmental biology, enhancers, skeletal development, human, mouse and zebrafish genetics, BAC transgenes, transcription factors, Gdf6, Bmp2, Bmp4, aortic valve disease, calcification, CRISPR, transgenic mice,Chromatin,Developmental biology,Gene regulation,Genetics,Genomics,Heart,Human Genetics

Research Description
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.

Much of our progress has been based on 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.

Currently, we are investigating the role of BMP2 regulation as a key potential mediator of calcific aortic valve disease (CAVD). BMP2 impacts this disease at 2 stages: first, in the embryo, during heart valve formation; and second, when it is upregulated in the adult aortic valve and likely stimulates the calcification of valve tissue. Along with our collaborator Dr. Melissa Rogers (Rutgers) we are determining the pre- and pos-transcriptional regulatory pathways that control BMP2 in the heart.

Ainoya, K, Moriguchi, T, Ohmori, S, Souma, T, Takai, J, Morita, M, Chandler, KJ, Mortlock, DP, Shimizu, R, Engel, JD, Lim, KC, Yamamoto, M. UG4 enhancer-driven GATA-2 and BMP4 complementation remedies the CAKUT phenotype in Gata2 hypomorphic mutant mice. Mol Cell Biol, , , 2012.

Mortlock, DP, Pregizer, S. Identifying functional annotation for noncoding genomic sequences. Curr Protoc Hum Genet, Chapter 1, Unit1.10, 2012.

Kruithof, BP, Fritz, DT, Liu, Y, Garsetti, DE, Frank, DB, Pregizer, SK, Gaussin, V, Mortlock, DP, Rogers, MB. An autonomous BMP2 regulatory element in mesenchymal cells. J Cell Biochem, 112(2), 666-74, 2011.

Zuvich, RL, Bush, WS, McCauley, JL, Beecham, AH, De Jager, PL, , , Ivinson, AJ, Compston, A, Hafler, DA, Hauser, SL, Sawcer, SJ, Pericak-Vance, MA, Barcellos, LF, Mortlock, DP, Haines, JL. Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis susceptibility: independent genetic signals in the CIITA-CLEC16A-SOCS1 gene complex. Hum Mol Genet, 20(17), 3517-24, 2011.

Anderson, L, Lowery, JW, Frank, DB, Novitskaya, T, Jones, M, Mortlock, DP, Chandler, RL, de Caestecker, MP. Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension. Am J Physiol Regul Integr Comp Physiol, 298(3), R833-42, 2010. PMCID:2838658

Collins, PL, Chang, S, Henderson, M, Soutto, M, Davis, GM, McLoed, AG, Townsend, MJ, Glimcher, LH, Mortlock, DP, Aune, TM. Distal regions of the human IFNG locus direct cell type-specific expression. J Immunol, 185(3), 1492-501, 2010. PMCID:2923829

Jiang, S, Chandler, RL, Fritz, DT, Mortlock, DP, Rogers, MB. Repressive BMP2 gene regulatory elements near the BMP2 promoter. Biochem Biophys Res Commun, 392(2), 124-8, 2010. PMCID:2822113

Reed, NP, Mortlock, DP. Identification of a distant cis-regulatory element controlling pharyngeal arch-specific expression of zebrafish gdf6a/radar. Dev Dyn, 239(4), 1047-60, 2010. PMCID:3110066

Chandler, KJ, Chandler, RL, Mortlock, DP. Identification of an ancient Bmp4 mesoderm enhancer located 46 kb from the promoter. Dev Biol, 327(2), 590-602, 2009. PMCID:2846791

Granero-Molt??, F, Weis, JA, Miga, MI, Landis, B, Myers, TJ, O''Rear, L, Longobardi, L, Jansen, ED, Mortlock, DP, Spagnoli, A. Regenerative effects of transplanted mesenchymal stem cells in fracture healing. Stem Cells, 27(8), 1887-98, 2009. PMCID:2765552

McCauley, JL, Zuvich, RL, Bradford, Y, Kenealy, SJ, Schnetz-Boutaud, N, Gregory, SG, Hauser, SL, Oksenberg, JR, Mortlock, DP, Pericak-Vance, MA, Haines, JL. Follow-up examination of linkage and association to chromosome 1q43 in multiple sclerosis. Genes Immun, 10(7), 624-30, 2009. PMCID:2765552

Pregizer, S, Mortlock, DP. Control of BMP gene expression by long-range regulatory elements. Cytokine Growth Factor Rev, 20(5-6), 509-15, 2009. PMCID:2787762

Boyle, S, Misfeldt, A, Chandler, KJ, Deal, KK, Southard-Smith, EM, Mortlock, DP, Baldwin, HS, de Caestecker, M. Fate mapping using Cited1-CreERT2 mice demonstrates that the cap mesenchyme contains self-renewing progenitor cells and gives rise exclusively to nephronic epithelia. Dev Biol, 313(1), 234-45, 2008. PMCID:2699557

Luppen, CA, Chandler, RL, Noh, T, Mortlock, DP, Frenkel, B. BMP-2 vs. BMP-4 expression and activity in glucocorticoid-arrested MC3T3-E1 osteoblasts: Smad signaling, not alkaline phosphatase activity, predicts rescue of mineralization. Growth Factors, 26(4), 226-37, 2008. PMCID:2846791

Chandler, KJ, Chandler, RL, Broeckelmann, EM, Hou, Y, Southard-Smith, EM, Mortlock, DP. Relevance of BAC transgene copy number in mice: transgene copy number variation across multiple transgenic lines and correlations with transgene integrity and expression. Mamm Genome, , , 2007.

Chandler, RL, Chandler, KJ, McFarland, KA, Mortlock, DP. Bmp2 transcription in osteoblast progenitors is regulated by a distant 3' enhancer located 156.3 kilobases from the promoter. Mol Cell Biol, 27(8), 2934-2951, 2007. PMCID:1899916

McCauley, JL, Kenealy, SJ, Margulies, EH, Schnetz-Boutaud, N, Gregory, SG, Hauser, SL, Oksenberg, JR, Pericak-Vance, MA, Haines, JL, Mortlock, DP. SNPs in Multi-species Conserved Sequences (MCS) as useful markers in association studies: a practical approach. BMC Genomics, 8, 266, 2007. PMCID:1959193

Spagnoli, A, O''Rear, L, Chandler, RL, Granero-Molto, F, Mortlock, DP, Gorska, AE, Weis, JA, Longobardi, L, Chytil, A, Shimer, K, Moses, HL. TGF-beta signaling is essential for joint morphogenesis. J Cell Biol, 177(6), 1105-17, 2007. PMCID:2064369

Deal, KK, Cantrell, VA, Chandler, RL, Saunders, TL, Mortlock, DP, Southard-Smith, EM. Distant regulatory elements in a Sox10-beta GEO BAC transgene are required for expression of Sox10 in the enteric nervous system and other neural crest-derived tissues. Dev Dyn, 235(5), 1413-32, 2006.

Portnoy, ME, McDermott, KJ, Antonellis, A, Margulies, EH, Prasad, AB, Kingsley, DM, Green, ED, Mortlock, DP, , . Detection of potential GDF6 regulatory elements by multispecies sequence comparisons and identification of a skeletal joint enhancer. Genomics, 86(3), 295-305, 2005.

Mortlock, DP. Comparative bioinformatics for mouse and human genes: getting started. Curr Protoc Hum Genet, Chapter 1, Unit 1.10, 2004.

Mortlock, Douglas P, Portnoy, Matthew E, Chandler, Ronald L, Green, Eric D, NISC, . Comparative sequence analysis of the Gdf6 locus reveals a duplicon-mediated chromosomal rearrangement in rodents and rapidly diverging coding and regulatory sequences. Genomics, 84(5), 814-23, 2004.

Mortlock, Douglas P, Guenther, Catherine, Kingsley, David M. A general approach for identifying distant regulatory elements applied to the Gdf6 gene. Genome Res, 13(9), 2069-81, 2003. PMCID:403689

Innis, Jeffrey W, Goodman, Frances R, Bacchelli, Chiara, Williams, Thomas M, Mortlock, Douglas P, Sateesh, Praveen, Scambler, Peter J, McKinnon, Wendy, Guttmacher, Alan E. A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome. Hum Mutat, 19(5), 573-4, 2002.

Goodman, F. R., Bachelli, C., Brady, A. F., Brueton, L. A., Fryns, J., Mortlock, D. P., Innis, J. W., Holmes, L. B., Donnenfeld, A. E., Feingold, M., Beemer, F. A., Hennekam, R. C. M., and P. J. Scambler. Novel HOXA13 mutations and the phenotypic spectrum of Hand-Foot-Genital Syndrome. American Journal of Human Genetics 67:192-202 (2000).

Mortlock, D. P., Sateesh, P. and Innis, J. W. Evolution of N-terminal sequences of the vertebrate Hoxa13 protein. Mammalian Genome 11:151-158 (2000).

Innis, J. W. and D. P. Mortlock. Limb development: molecular dysmorphology is at hand! Clinical Genetics 53:337-348 (1998).

Mortlock, D. P. and J. W. Innis. Mutation in HOXA13 in Hand-Foot-Genital syndrome. Nature Genetics 15: 179-180 (1997).

Innis, J. W., S. M. Darling, K. Kazen-Gillespie, L. C. Post, D. P. Mortlock, T. Yang. Orientation of the Hoxa complex and placement of the Hd locus distal to Hoxa2 on mouse Chromosome 6. Mammalian Genome 7: 216-217 (1996).

Mortlock, D. P., L. C. Post, J. W. Innis. The molecular basis of hypodactyly (Hd): a deletion in Hoxa13 leads to arrest of digital arch formation. Nature Genetics 13: 284-289 (1996).

Mortlock, D. P., M. R. Nelson, J. W. Innis. An efficient method for isolating putative promoters and 5'-transcribed sequences from large genomic clones. Genome Research 6: 327-335 (1996).

Bespalova, I. N., Q. Farjo, D. P. Mortlock, A. U. Jackson, M. H. Meisler, A. Swaroop, M. Burmeister. Mapping of the neural retina leucine zipper gene, Nrl, to mouse chromosome 14. Mammalian Genome 4: 618-620 (1993).

Mortlock, D., E. B. Keller, C. J. Ziegra, and M. J. Suter. High efficiency transfection of monkey kidney COS-1 cells. Journal of Tissue Culture Methods 15: 176-180 (1993).

ffrench-Constant, R. H., D. P. Mortlock, C. D. Shaffer, R. J. MacIntyre, R. T. Roush. Cloning of cyclodiene insecticide resistance: an invertebrate GABA receptor. Proceedings of the National Academy of Sciences 88: 7209-7213 (1991).

ffrench-Constant, R. H., R. T. Roush, D. Mortlock, G. P. Dively. Isolation of dieldrin resistance from field populations of Drosophila melanogaster (Diptera: Drosophilidae). Journal of Economic Entomology 83(5): 1733-1737 (1990).

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