Warren E. Zimmer, PhD
Scott Exter Professor
Director of Medical Science Graduate Program
Director of MD Plus Program
Director of Summer Research Program
Education and Post-Graduate Training
PhD Baylor College of Medicine
Postdoctoral Studies: Vanderbilt University College of Medicine
Development and Differentiation, Mechanisms of Transcription Factor Action
Our research interests are directed towards understanding the complex mechanisms which regulate the expression of specific gene sequences in development. We have focused our studies upon the factors that influence the smooth muscle component of the developing gastrointestinal (G.I.) tract. It has been shown that smooth muscle cells are predominantly derived from mesodermal precursor cells, however the factors regulating the selection of the smooth muscle myogenic pathway is not well defined.
We have shown that there is a definant lineage of smooth muscle during development and that the terminal differentiation of these cells requires an upregulation in expression of the trans-factor Serum Response Factor (SRF). This factor is known to work in conjunction with other partner proteins to engage cell specific transcriptional responses. Current studies in the lab are focused upon determining the identity of these partner proteins and showing how they work with SRF to achieve smooth muscle terminal differentiation. We have initiated these experiments looking at the mammalian homologs of the Drosophila bagpipe protein, termed Nkx3.1 and Nkx3.2. The studies utilize molecular and cellular biological techniques in combination with transgenic mouse knockout technologies to directly examine the ability of these factors to influence development.
Additionally, our recent transgenic studies have allowed an investigation of signaling pathways potentially governing smooth muscle cell differentiation. Interestingly, these studies have shown a convergence of pathways upon SRF in smooth muscle and these pathways may be influential in developing prostate and osteogenesis. We believe that our studies will reveal molecular mechanisms which underlie changes in metabolism growth control in smooth muscle which are associated with the primary physiological responses of these cells in vascular and viscual injury and disease states. In addition we will gain knowledge of mechanisms that are influential for bone and prostate development and disease, such as prostate cancer.
- Kovacs AM, Zimmer WE. Cell specific transcription of the smooth muscle g-actin gene requires both positive and negative acting cis-elements. Gene Express. 7:115-129, 1998.
- Browning CL, Culberson DE, Aragon IV, Fillmore RA, Croissant JD, Schwartz RJ, Zimmer WE. The developmentally regulated expression of serum response factor plays a major role in the regulation of smooth muscle specific gene regulation. Dev Biol. 194:18-37, 1998.
- Vacik J, Dean BS, Zimmer WE, Dean DA. Cell specific nuclear of plasmid DNA. Gene Ther. 6:1006-1014, 1999.
- Carson JA, Fillmore RA, Schwartz RJ, Zimmer WE. The smooth muscle gamma-actin gene promoter is a molecular target for the mouse bagpipe homologue, mNkx 3.1,and serum response factor. J Biol Chem 275:39061-39072, 2000.
- Kakhniashvili DG, Chaudrary T, Zimmer WE, Bencsanth FA, Jardin I, Goodman SR. Spectrin is an E2/E3 ubiquitin conjugating/ligating enzyme. Biochemistry 40:11630-11642, 2001.
- Hirschi KK, Lai L, Belaguli NS, Dean DA, Schwartz RJ, Zimmer WE. Transforming growth factor-beta induction of smooth muscle cell phenotype requires transcriptional and post-transcriptional control of serum repsonse factor. J Biol Chem. 2002 Feb 22; 277(8): 6287-95.
- Filmore RA, Dean DA, Zimmer WE. The smooth muscle gamma-actin gene is androgen responsive in prostate epithelia. Gene Expr. 2002; 10(5-6): 201-11.
- Carson JA, Culberson DE, Thompson RW, Fillmore RA, Zimmer W. Smooth muscle gamma-actin promoter regulation by RhoA and serum response factor signaling. Biochim Biophys Acta. 2003 Jul 28; 1628(2): 133-9.
- Vlahopoulos S, Zimmer WE, Jenster G, Balguli NS, Balk SP, Brinkmann AO, Lanz RB, Zoumpourlis VC, Schwartz RJ. Recruitment of the androgen receptor via serum response factor facilitates expression of a myogenic gene. J Biol Chem. 2005 Mar 4; 280(9): 7786-92.
- Takamoto N, You LR, Moses K, Chiang C, Zimmer WE, Schwartz RJ, DeMayo FJ, Tsai MJ, Tsai SY. COUP-TFII is essential for radial and anteroposterior patterning of the stomach. Development. 2005 May; 132(9): 2179-89.
- Dean DA, Strong DD, Zimmer WE. Nuclear entry of nonviral vectors. Gene Ther. 2005 Jun; 12(11): 881-90. Review.
- Stanfel MN, Moses KA, Carson JA, Zimmer DB, DeMayo F, Schwartz RJ, Zimmer WE. Expression of an Nkx3.1-CRE gene using ROSA26 reporter mice. Genesis. 2006 Nov; 44(11): 550-5.
- Akintola AD, Crislip ZL, Catania JM, Chen G, Zimmer WE, Burghardt RC, Parrish AR. Promoter methylation is associated with the age-dependent loss of N-cadherin in the rat kidney. Am J Physiol Renal Physiol. 2008 Jan; 294(1): F170-6.
- Zhang Y, Fillmore RA, Zimmer WE. Structural and functional analysis of domains mediating interaction between the bagpipe homologue, Nkx3.1 and serum response factor. Exp Biol Med (Maywood). 2008 Mar; 233(3): 297-309.
- Young JL, Zimmer WE, Dean DA. Smooth muscle-specific gene delivery in the vasculature based on restriction of DNA nuclear import. Exp Biol Med (Maywood). 2008 Jul; 233(7): 840-8.
- Verzi MP, Stanfel MN, Moses KA, Kim BM, Zhang Y, Schwartz RJ, Shivdasani RA, Zimmer WE. Role of the homeodomain transcription factor Bapx1 in mouse distal stomach development. Gastroenterology. 2009 May; 136(5): 1701-10.