Adjunct Assistant Professor of Pharmacology
VUMC 9435-A MRB4 Langford 2213 Garland Ave, Nashville, TN, 37232
Research DescriptionThe goal of our laboratory is to understand the molecular mechanisms governing cardiac development and remodeling. The early linear heart tube is connected to a symmetrical system of aortic arch arteries. This primitive structure is remodeled into the mature cardiovascular system with separate high and low pressure circulation connected to the heart through a single aortic arch and pulmonary trunk. This remodeling is mediated by a population of migratory cells known as the cardiac neural crest. These cells directly contribute to the aortic arch arteries by differentiating into smooth muscle cells. Additional roles of the cardiac neural crest in determining which primitive arteries contribute to the mature vessels are less clearly understood.
Using the mouse as a model system we are examining the role of a class of signaling proteins known as semaphorins in neural crest mediated cardiovascular remodeling. Semaphorins were initially characterized as neural pathfinding molecules. Intriguingly, targeted ablation of Semaphorin 3C (Sema3C) results in cardiovascular malformations and not neural pathfinding defects. Sema3C homozygous null embryos exhibit interruption of the aorta and a condition called persistent truncus arteriosus in which the aorta and pulmonary artery fail to fully separate. We hypothesize that the cardiac defects observed are secondary to defects in the cardiac neural crest. Preliminary experiments indicate that neural crest migration, while perturbed, is not grossly deficient in Sema3C null animals. This suggests that the neural crest defect is not in migration but in differentiation, proliferation, or survival. We are currently assessing these aspects in the Sema3C null embryos.
Semaphorins signal through receptor complexes composed of two classes of transmembrane proteins called Neuropilins and Plexins. We have identified PlexinA2 as a putative co-receptor for Sema3C in cardiac neural crest cells. In order to demonstrate a requirement for PlexinA2 in the neural crest, we are taking advantage of dominant negative receptor expression to assess the role of Plexin signaling in neural crest cells. These experiments will allow us to determine the global requirement for functional plexin signaling in the cardiac neural crest. We are also generating conditional alleles of Sema3C and PlexinA2 to determine the tissue specific requirements for each gene.
Our long term goal is to better understand the complex role of neural crest cells in cardiac development and disease. The importance of these experiments is underscored by the observation that cardiovascular developmental defects are among the most prevalent developmental defects seen in children, occurring at rates as high as 1 in 100 births.
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- Jiao K, Langworthy M, Batts L, Brown CB, Moses HL, Baldwin HS. Tgfbeta signaling is required for atrioventricular cushion mesenchyme remodeling during in vivo cardiac development. Development [print-electronic]. 2006 Nov; 133(22): 4585-93. PMID: 17050629, PII: dev.02597, DOI: 10.1242/dev.02597, ISSN: 0950-1991.
- Brown CB, Baldwin HS. Neural crest contribution to the cardiovascular system. Adv. Exp. Med. Biol. 2006; 589: 134-54. PMID: 17076279, DOI: 10.1007/978-0-387-46954-6_8, ISSN: 0065-2598.
- Marlow MS, Brown CB, Barnett JV, Krezel AM. Solution structure of the chick TGFbeta type II receptor ligand-binding domain. J. Mol. Biol. 2003 Feb 2/28/2003; 326(4): 989-97. PMID: 12589747, PII: S0022283603000238, ISSN: 0022-2836.
- Gitler AD, Brown CB, Kochilas L, Li J, Epstein JA. Neural crest migration and mouse models of congenital heart disease. Cold Spring Harb. Symp. Quant. Biol. 2002; 67: 57-62. PMID: 12858524, ISSN: 0091-7451.
- Brown CB, Feiner L, Lu MM, Li J, Ma X, Webber AL, Jia L, Raper JA, Epstein JA. PlexinA2 and semaphorin signaling during cardiac neural crest development. Development. 2001 Aug; 128(16): 3071-80. PMID: 11688557, ISSN: 0950-1991.
- Feiner L, Webber AL, Brown CB, Lu MM, Jia L, Feinstein P, Mombaerts P, Epstein JA, Raper JA. Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption. Development. 2001 Aug; 128(16): 3061-70. PMID: 11688556, ISSN: 0950-1991.
- Marlow MS, Chim N, Brown CB, Barnett JV, Krezel AM. 1H, 13C, and 15N backbone assignments of the ligand binding domain of TGFbeta type II receptor [letter]. J. Biomol. NMR. 2000 Aug; 17(4): 349-50. PMID: 11014599, ISSN: 0925-2738.
- Lai YT, Beason KB, Brames GP, Desgrosellier JS, Cleggett MC, Shaw MV, Brown CB, Barnett JV. Activin receptor-like kinase 2 can mediate atrioventricular cushion transformation. Dev. Biol. 2000 Jun 6/1/2000; 222(1): 1-11. PMID: 10885742, PII: S0012-1606(00)99698-2, DOI: 10.1006/dbio.2000.9698, ISSN: 0012-1606.
- Epstein JA, Li J, Lang D, Chen F, Brown CB, Jin F, Lu MM, Thomas M, Liu E, Wessels A, Lo CW. Migration of cardiac neural crest cells in Splotch embryos. Development. 2000 May; 127(9): 1869-78. PMID: 10751175, ISSN: 0950-1991.
- Brown CB, Drake CJ, Barnett JV. Antibodies directed against the chicken type II TGFbeta receptor identify endothelial cells in the developing chicken and quail. Dev. Dyn. 1999 May; 215(1): 79-85. PMID: 10340759, PII: 10.1002/(SICI)1097-0177(199905)215:1<79::AID-DVDY9>3.0.CO;2-H, DOI: 10.1002/(SICI)1097-0177(199905)215:1<79::AID-DVDY9>3.0.CO;2-H, ISSN: 1058-8388.
- Brown CB, Boyer AS, Runyan RB, Barnett JV. Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. Science. 1999 Mar 3/26/1999; 283(5410): 2080-2. PMID: 10092230, ISSN: 0036-8075.
- Brown CB, Boyer AS, Runyan RB, Barnett JV. Antibodies to the Type II TGFbeta receptor block cell activation and migration during atrioventricular cushion transformation in the heart. Dev. Biol. 1996 Mar 3/15/1996; 174(2): 248-57. PMID: 8631497, PII: S0012-1606(96)90070-6, DOI: 10.1006/dbio.1996.0070, ISSN: 0012-1606.