Douglas P. Mortlock, Ph.D.

Adjunct Assistant Professor
Faculty Appointments
Adjunct Assistant Professor of Molecular Physiology & Biophysics
Ph.D., Human Genetics, University of Michigan, Ann Arbor, MichiganB.A., Biological Sciences, Cornell University, Ithaca, New York
Office Address
519 Light Hall (Center for Human Genetics Research)
Vanderbilt University Medical Center
Nashville, TN 37232-0700
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.

Recently, I have been heavily involved in developing CRISPR-based gene editing methods into routine services for the Vanderbilt transgenic mouse core (TMESCSR). I continue to collaborate with several Vanderbilt investigators in their efforts to use CRISPR to engineer mutations in mice or cultured cell lines.
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
Muinos-López E, Ripalda-Cemboráin P, López-Martínez T, González-Gil AB, Lamo-Espinosa JM, Valentí A, Mortlock DP, Valentí JR, Prósper F, Granero-Moltó F. Hypoxia and Reactive Oxygen Species Homeostasis in Mesenchymal Progenitor Cells Define a Molecular Mechanism for Fracture Nonunion. Stem Cells [print-electronic]. 2016 Jun 6/2/2016; PMID: 27250101, DOI: 10.1002/stem.2399, ISSN: 1549-4918.

Pregizer SK, Mortlock DP. Dynamics and cellular localization of Bmp2, Bmp4, and Noggin transcription in the postnatal mouse skeleton. J. Bone Miner. Res. 2015 Jan; 30(1): 64-70. PMID: 25043193, DOI: 10.1002/jbmr.2313, ISSN: 1523-4681.

Yutzey KE, Demer LL, Body SC, Huggins GS, Towler DA, Giachelli CM, Hofmann-Bowman MA, Mortlock DP, Rogers MB, Sadeghi MM, Aikawa E. Calcific aortic valve disease: a consensus summary from the Alliance of Investigators on Calcific Aortic Valve Disease. Arterioscler. Thromb. Vasc. Biol [print-electronic]. 2014 Nov; 34(11): 2387-93. PMID: 25189570, PMCID: PMC4199903, PII: ATVBAHA.114.302523, DOI: 10.1161/ATVBAHA.114.302523, ISSN: 1524-4636.

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. Recurrent tissue-specific mtDNA mutations are common in humans. PLoS Genet [print-electronic]. 2013 Nov; 9(11): e1003929. PMID: 24244193, PMCID: PMC3820769, PII: PGENETICS-D-13-01891, DOI: 10.1371/journal.pgen.1003929, ISSN: 1553-7404.

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 bone morphogenetic protein 4 complementation remedies the CAKUT phenotype in Gata2 hypomorphic mutant mice. Mol. Cell. Biol [print-electronic]. 2012 Jun; 32(12): 2312-22. PMID: 22493062, PMCID: PMC3372261, PII: MCB.06699-11, DOI: 10.1128/MCB.06699-11, ISSN: 1098-5549.

Mortlock DP, Pregizer S. Identifying functional annotation for noncoding genomic sequences. Curr Protoc Hum Genet. 2012 Jan; Chapter 1: Unit1.10. PMID: 22241655, DOI: 10.1002/0471142905.hg0110s72, ISSN: 1934-8258.

Clendenning DE, Mortlock DP. The BMP ligand Gdf6 prevents differentiation of coronal suture mesenchyme in early cranial development. PLoS ONE [print-electronic]. 2012; 7(5): e36789. PMID: 22693558, PMCID: PMC3365063, PII: PONE-D-12-01549, DOI: 10.1371/journal.pone.0036789, ISSN: 1932-6203.

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 [print-electronic]. 2011 Sep 9/1/2011; 20(17): 3517-24. PMID: 21653641, PMCID: PMC3153306, PII: ddr250, DOI: 10.1093/hmg/ddr250, ISSN: 1460-2083.

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. 2011 Feb; 112(2): 666-74. PMID: 21268088, PMCID: PMC4198144, DOI: 10.1002/jcb.22975, ISSN: 1097-4644.

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 [print-electronic]. 2010 Aug 8/1/2010; 185(3): 1492-501. PMID: 20574006, PMCID: PMC2923829, PII: jimmunol.1000124, DOI: 10.4049/jimmunol.1000124, ISSN: 1550-6606.

Reed NP, Mortlock DP. Identification of a distant cis-regulatory element controlling pharyngeal arch-specific expression of zebrafish gdf6a/radar. Dev. Dyn. 2010 Apr; 239(4): 1047-60. PMID: 20201106, PMCID: PMC3110066, DOI: 10.1002/dvdy.22251, ISSN: 1097-0177.

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 [print-electronic]. 2010 Mar; 298(3): R833-42. PMID: 20042692, PMCID: PMC2838658, PII: 00534.2009, DOI: 10.1152/ajpregu.00534.2009, ISSN: 1522-1490.

Jiang S, Chandler RL, Fritz DT, Mortlock DP, Rogers MB. Repressive BMP2 gene regulatory elements near the BMP2 promoter. Biochem. Biophys. Res. Commun [print-electronic]. 2010 Feb 2/5/2010; 392(2): 124-8. PMID: 20060812, PMCID: PMC2822113, PII: S0006-291X(09)02555-8, DOI: 10.1016/j.bbrc.2009.12.157, ISSN: 1090-2104.

Pregizer S, Mortlock DP. Control of BMP gene expression by long-range regulatory elements. Cytokine Growth Factor Rev [print-electronic]. 2009 Oct; 20(5-6): 509-15. PMID: 19900834, PMCID: PMC2787762, PII: S1359-6101(09)00086-0, DOI: 10.1016/j.cytogfr.2009.10.011, ISSN: 1879-0305.

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 [print-electronic]. 2009 Oct; 10(7): 624-30. PMID: 19626040, PMCID: PMC2765552, PII: gene200953, DOI: 10.1038/gene.2009.53, ISSN: 1476-5470.

Granero-Moltó 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. 2009 Aug; 27(8): 1887-98. PMID: 19544445, PMCID: PMC3426453, DOI: 10.1002/stem.103, ISSN: 1549-4918.

Chandler KJ, Chandler RL, Mortlock DP. Identification of an ancient Bmp4 mesoderm enhancer located 46 kb from the promoter. Dev. Biol [print-electronic]. 2009 Mar 3/15/2009; 327(2): 590-602. PMID: 19159624, PMCID: PMC2846791, PII: S0012-1606(08)01471-1, DOI: 10.1016/j.ydbio.2008.12.033, ISSN: 1095-564X.

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. 2008 Aug; 26(4): 226-37. PMID: 19021035, PMCID: PMC3760374, PII: 795057432, DOI: 10.1080/08977190802277880, ISSN: 0897-7194.

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 [print-electronic]. 2008 Jan 1/1/2008; 313(1): 234-45. PMID: 18061157, PMCID: PMC2699557, PII: S0012-1606(07)01457-1, DOI: 10.1016/j.ydbio.2007.10.014, ISSN: 1095-564X.

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 [print-electronic]. 2007 Oct; 18(10): 693-708. PMID: 17882484, PMCID: PMC3110064, DOI: 10.1007/s00335-007-9056-y, ISSN: 0938-8990.

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. 2007 Jun 6/18/2007; 177(6): 1105-17. PMID: 17576802, PMCID: PMC2064369, PII: jcb.200611031, DOI: 10.1083/jcb.200611031, ISSN: 0021-9525.

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 [print-electronic]. 2007 Apr; 27(8): 2934-51. PMID: 17283059, PMCID: PMC1899916, PII: MCB.01609-06, DOI: 10.1128/MCB.01609-06, ISSN: 0270-7306.

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. 2007; 8: 266. PMID: 17683615, PMCID: PMC1959193, PII: 1471-2164-8-266, DOI: 10.1186/1471-2164-8-266, ISSN: 1471-2164.

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. 2006 May; 235(5): 1413-32. PMID: 16586440, DOI: 10.1002/dvdy.20769, ISSN: 1058-8388.

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. 2005 Sep; 86(3): 295-305. PMID: 15979840, PII: S0888-7543(05)00131-X, DOI: 10.1016/j.ygeno.2005.05.003, ISSN: 0888-7543.

Mortlock DP, Portnoy ME, Chandler RL, , Green ED. Comparative sequence analysis of the Gdf6 locus reveals a duplicon-mediated chromosomal rearrangement in rodents and rapidly diverging coding and regulatory sequences. Genomics. 2004 Nov; 84(5): 814-23. PMID: 15475260, PII: S0888-7543(04)00198-3, DOI: 10.1016/j.ygeno.2004.07.009, ISSN: 0888-7543.

Mortlock DP. Comparative bioinformatics for mouse and human genes: getting started. Curr Protoc Hum Genet. 2004 Sep; Chapter 1: Unit 1.10. PMID: 18428352, DOI: 10.1002/0471142905.hg0110s41, ISSN: 1934-8258.

Mortlock DP, Guenther C, Kingsley DM. A general approach for identifying distant regulatory elements applied to the Gdf6 gene. Genome Res [print-electronic]. 2003 Sep; 13(9): 2069-81. PMID: 12915490, PMCID: PMC403689, PII: 1306003, DOI: 10.1101/gr.1306003, ISSN: 1088-9051.

Innis JW, Goodman FR, Bacchelli C, Williams TM, Mortlock DP, Sateesh P, Scambler PJ, McKinnon W, Guttmacher AE. A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome. Hum. Mutat. 2002 May; 19(5): 573-4. PMID: 11968094, DOI: 10.1002/humu.9036, ISSN: 1098-1004.