Denise Marciano, M.D., Ph.D.
Assistant Professor

Research in the Marciano laboratory is focused on understanding the cellular and molecular mechanisms of tubular and glomerular formation in health and disease.

Cellular and molecular mechanisms of tubulogenesis

One of the fundamental questions of developmental biology is: how do a group of cells orchestrate the complex changes, including proliferation, migration, sorting, and differentiation to form a polarized tubule? This is especially important in human biology as defects in these processes lead to diseases such as polycystic kidney disease. Currently our laboratory is studying the role of cell-cell adhesion molecules in tubulogenesis and kidney morphogenesis. We are using an 3-dimensional cell culture model and mouse genetics to study these processes in developing kidney tubules.

One family of cell-cell adhesion receptors, the cadherins, interacts via their extracellular domains to form adherens junctions between neighboring cells. Key regulators of cadherins are p120 catenin (p120ctn) and b-catenin, which bind to intracellular regions of cadherins and regulate cell-cell adhesion, signal transduction and gene transcription. We recently found that absence of the cadherin regulator p120 catenin (p120ctn) in mice leads to decreased cadherin levels with abnormal morphologies of early tubule structures (Marciano et al., 2011).  Furthermore, p120ctn mutant mice develop cystic kidney disease, with markedly increased tubule diameter, cellular proliferation, and detached luminal cells. We are currently investigating the molecular mechanisms by which p120ctn and cadherin signaling control tubule formation and diameter.

Another focus of the laboratory is to identify how apical basal polarity and lumen formation is initiated in developing renal tubules. We have recently identified a mouse model in which these processes are disrupted (Yang et al., 2013). Mice lacking Afadin, a nectin adaptor and Rap1 effector, have defects in establishing an apical surface and forming a continuous lumen. We are investigating the signaling pathways that mediate these defects and are identifying other essential pathways in initiation of tubulogenesis. We expect that these results will give insight into childhood developmental disorders such as congenital renal dysplasia. In addition, knowledge of these mechanisms may be important in acquired renal diseases of tubules.

Role of cell-cell adhesion in glomerular formation and function

Kidneys filter blood through highly specialized structures called glomeruli. The regulation of glomerular filtration is essential for life, and defects in this process cause glomerular disease and kidney failure. In recent studies we have found that mice lacking p120ctn in glomeruli develop focal segmental glomerulosclerosis, a common cause of renal failure in humans that is attributed to defects in the permeability barrier. We are currently examining the role of p120 catenin and other adhesion proteins for their role in the formation and maintenance of the filtration barrier using mouse genetics, cell culture, RNAi, and biochemistry. We expect that understanding these processes will give insight into normal glomerular development and the pathogenesis of various glomerular diseases.

 

Graduate School

Rockefeller University (1999)

Medical School

Cornell University Medical College (2001)

Residency

University of California, San Francisco (2004), Internal Medicine

Fellowship

University of California at San Francisco (2007), Nephrology

• Cell polarity
• Kidney development and disease
• Tubulogenesis

Featured Publications

De novo lumen formation and elongation in the developing nephron: a central role for afadin in apical polarity.

Yang Z, Zimmerman S, Brakeman PR, Beaudoin GM, Reichardt LF, Marciano DK Development 2013 Mar

p120 catenin is required for normal renal tubulogenesis and glomerulogenesis.

Marciano DK, Brakeman PR, Lee CZ, Spivak N, Eastburn DJ, Bryant DM, Beaudoin GM, Hofmann I, Mostov KE, Reichardt LF Development 2011 May 138 10 2099-109

Assembling filamentous phage occlude pIV channels.

Marciano DK, Russel M, Simon SM Proc. Natl. Acad. Sci. U.S.A. 2001 Jul 98 16 9359-64

An aqueous channel for filamentous phage export.

Marciano DK, Russel M, Simon SM Science 1999 May 284 5419 1516-9

Developing renal tubules orient cell division via Afadin to position the tubule lumen

Gao L, Zhufeng, Y, hiremath C, Zimmerman SE, Long B, Brakeman PR, Mostov KE, Bryant DM, Luby-Phelps K, Marciano DK Development 2017 In press

Role of CD34 family members in lumen formation in the developing kidney.

Yang Z, Zimmerman SE, Tsunezumi J, Braitsch C, Trent C, Bryant DM, Cleaver O, González-Manchón C, Marciano DK Dev. Biol. 2016 Aug

A holey pursuit: lumen formation in the developing kidney.

Marciano DK Pediatr. Nephrol. 2016 Feb

A novel method that improves sensitivity of protein detection in PAGE and western blot.

Vallejo-Illarramendi A, Marciano DK, Reichardt LF Electrophoresis 2013 Feb

cor, a Novel Carbon Monoxide Resistance Gene, Is Essential for Mycobacterium tuberculosis Pathogenesis.

Zacharia VM, Manzanillo PS, Nair VR, Marciano DK, Kinch LN, Grishin NV, Cox JS, Shiloh MU MBio 2013 4 6

The basement membrane of hair follicle stem cells is a muscle cell niche.

Fujiwara H, Ferreira M, Donati G, Marciano DK, Linton JM, Sato Y, Hartner A, Sekiguchi K, Reichardt LF, Watt FM Cell 2011 Feb 144 4 577-89

• March of Dimes Basil O'Connor Scholar
  (2013)
• Norman S. Coplon Extramural Grant
  (2013)
• K08 and NKF Young Investigator Awards
  (2008)
• NRSA F32 grant
  (2005)
• Janet M. Glasgow Memorial Achievement Award
  Graduated in top ten students at Cornell Univ Medical College (2001)
• Magna cum laude and Phi Beta Kappa, Dartmouth College
  (1993)

• American Society of Nephrology
• National Kidney Foundation