Raymond E. Keller

Primary Appointment

  • Alumni Council Thomas Jefferson of Biology, Biology

Contact

Research Interest(s)

Cellular and molecular mechanisms of morphogenesis

Research Description

The goal of our research is to learn the cellular, molecular and biomechanical mechanisms underlying morphogenetic movements during embryogenesis. One of the fundamental problems in developmental biology is determining what local cellular activities underlie the morphogenesis of cell populations. Analysis of this problem requires an integrated, multilevel approach. We examine the cell motility or shape changes that constitute the "motor" of morphogenetic movement with time lapse recording of low light videomicroscopy, or with confocal microscopy of labeled cells both in the whole embryo and explants. We learn how these types of cell motility generate forces, and determine the mechanical properties of the tissues transmitting these forces, by correlating videomicroscopy of cell behavior with mechanical measurements, using a computer-controlled biomechanical measuring device. To understand the molecular mechanisms of cell motility, and the biomechanics of how it is harnessed, we use pharmacologcal and molecular biological manipulations to alter the function of molecular components and analyze the resulting changes in cell behavior, force production, and mechanical properties of the tissue. Since the mechanical function of a region-specific cell motility is dependent on the spatial and temporal pattern of its expression, we test what tissue interactions induce and pattern specific cell motilities by making microsurgical rearrangements of inducing and responding tissues. Since movements feedback on inductions, we also physically block movements and monitor changes in patterning of motility.

Our analysis of the convergent extension movements in the embryo of the frog, Xenopus laevis, serves as an example of this approach. The dorsal tissues of the vertebrate embryo narrow (converge) and elongate (extend) greatly during gastrulation and neurulation in movements collectively called "convergent extension." We used videomicroscopy of fluorescently labeled cells to show that cells bias their protrusive activity in the mediolateral direction, exert traction on adjacent cells in this direction, and pull themselves between one another along the mediolateral axis, to form a longer, narrower array. Mechanical measurements showed that the tissue becomes stiffer as it extends, enabling it to push strongly enough to stretch the remaining passive tissues of the embryo without buckling. Our current work seeks to learn the molecular and mechanical basis of this directed protrusive activity and stiffening, and also how these properties are induced. We inject RNAs coding for proteins that act as dominant inhibitors of molecules thought to be important in organizing the directed protrusive activity, along with RNA coding for green fluorescent protein (GFP). This enables us to visualize the resulting changes in behavior of the affected cells, with low light fluorescence videomicroscopy. Correlated changes in the forces produced and in tissue mechanics are measured, and changes in the terminal cell phenotype are monitored with molecular marker expression. With this multilevel, integrated approach, we can perturb a molecular function and directly analyze the effect on cell motility, tissue mechanics, patterning, and cell differentiation, enabling us to learn what components function in a particular morphogenetic event, and the mechanism of that function.

Selected Publications

  • Barton C, McMillian W, Raza S, Keller R. Hemopericardium in a patient treated with dabigatran etexilate. Pharmacotherapy. 2012;32(5): e103-7. PMID: 22488474
  • Keller S, Gilbert K, Fields P, Taylor D. Bayesian inference of a complex invasion history revealed by nuclear and chloroplast genetic diversity in the colonizing plant, Silene latifolia. Molecular ecology. 2012;21(19): 4721-34. PMID: 22943057
  • Keller S, Levsen N, Olson M, Tiffin P. Local adaptation in the flowering-time gene network of balsam poplar, Populus balsamifera L. Molecular biology and evolution. 2012;29(10): 3143-52. PMID: 22513286
  • Lansey M, Walker N, Hargett S, Stevens J, Keller S. Deletion of Rab GAP AS160 modifies glucose uptake and GLUT4 translocation in primary skeletal muscles and adipocytes and impairs glucose homeostasis. American journal of physiology. Endocrinology and metabolism. 2012;303(10): E1273-86. PMID: 23011063 | PMCID: PMC3517634
  • Olson M, Levsen N, Soolanayakanahally R, Guy R, Schroeder W, Keller S, Tiffin P. The adaptive potential of Populus balsamifera L. to phenology requirements in a warmer global climate. Molecular ecology. 2012. PMID: 23094714
  • Cutchins A, Harmon D, Kirby J, Doran A, Oldham S, Skaflen M, Klibanov A, Meller N, Keller S, Garmey J, McNamara C. Inhibitor of differentiation-3 mediates high fat diet-induced visceral fat expansion. Arteriosclerosis, thrombosis, and vascular biology. 2011;32(2): 317-24. PMID: 22075252 | PMCID: PMC3262109
  • Galkina E, Butcher M, Keller S, Goff M, Bruce A, Pei H, Sarembock I, Sanders J, Nagelin M, Srinivasan S, Kulkarni R, Hedrick C, Lattanzio F, Dobrian A, Nadler J, Ley K. Accelerated atherosclerosis in Apoe-/- mice heterozygous for the insulin receptor and the insulin receptor substrate-1. Arteriosclerosis, thrombosis, and vascular biology. 2011;32(2): 247-56. PMID: 22199371
  • Hinault C, Kawamori D, Liew C, Maier B, Hu J, Keller S, Mirmira R, Scrable H, Kulkarni R. Δ40 Isoform of p53 controls β-cell proliferation and glucose homeostasis in mice. Diabetes. 2011;60(4): 1210-22. PMID: 21357466 | PMCID: PMC3064094
  • Keller S, Engen D, Bauer B, Holmes D, Rihal C, Lennon R, Loehrer L, Wahner-Roedler D. Feasibility and effectiveness of massage therapy for symptom relief in cardiac catheter laboratory staff: a pilot study. Complementary therapies in clinical practice. 2011;18(1): 4-9. PMID: 22196566
  • Keller S, Soolanayakanahally R, Guy R, Silim S, Olson M, Tiffin P. Climate-driven local adaptation of ecophysiology and phenology in balsam poplar, Populus balsamifera L. (Salicaceae). American journal of botany. 2011;98(1): 99-108. PMID: 21613088
  • Keller S, Wiener R. What are we studying? Student jurors, community jurors, and construct validity. Behavioral sciences & the law. 2011;29(3): 376-94. PMID: 21766327
  • Kemp B, Howell N, Gray J, Keller S, Nass R, Padia S. Intrarenal ghrelin infusion stimulates distal nephron-dependent sodium reabsorption in normal rats. Hypertension. 2011;57(3): 633-9. PMID: 21220707 | PMCID: PMC3041845
  • Padia S, Kemp B, Howell N, Keller S, Gildea J, Carey R. Mechanisms of dopamine D(1) and angiotensin type 2 receptor interaction in natriuresis. Hypertension. 2011;59(2): 437-45. PMID: 22203736 | PMCID: PMC3279722
  • Sloan D, Keller S, Berardi A, Sanderson B, Karpovich J, Taylor D. De novo transcriptome assembly and polymorphism detection in the flowering plant Silene vulgaris (Caryophyllaceae). Molecular ecology resources. 2011;12(2): 333-43. PMID: 21999839
  • Keller S, Taylor D. Genomic admixture increases fitness during a biological invasion. Journal of evolutionary biology. 2010;23(8): 1720-31. PMID: 20626546
  • Roland A, Nunemaker C, Keller S, Moenter S. Prenatal androgen exposure programs metabolic dysfunction in female mice. The Journal of endocrinology. 2010;207(2): 213-23. PMID: 20713501
  • Voiculescu O, Bertocchini F, Wolpert L, Keller R, Stern C. The amniote primitive streak is defined by epithelial cell intercalation before gastrulation. Nature. 2007;449(7165): 1049-52. PMID: 17928866
  • Davidson L, Keller R. Neural tube closure in Xenopus laevis involves medial migration, directed protrusive activity, cell intercalation and convergent extension. Development (Cambridge, England). 1999;126(20): 4547-56. PMID: 10498689
  • Davidson L, Oster G, Keller R, Koehl M. Measurements of mechanical properties of the blastula wall reveal which hypothesized mechanisms of primary invagination are physically plausible in the sea urchin Strongylocentrotus purpuratus. Developmental biology. 1999;209(2): 221-38. PMID: 10328917
  • Elul T, Koehl M, Keller R. Patterning of morphogenetic cell behaviors in neural ectoderm of Xenopus laevis. Annals of the New York Academy of Sciences. 1999;857 248-51. PMID: 9917849
  • Minsuk S, Keller R. Dorsal mesoderm has a dual origin and forms by a novel mechanism in Hymenochirus, a relative of Xenopus. Developmental biology. 1996;174(1): 92-103. PMID: 8626024
  • Winklbauer R, Keller R. Fibronectin, mesoderm migration, and gastrulation in Xenopus. Developmental biology. 1996;177(2): 413-26. PMID: 8806820
  • Moore S, Keller R, Koehl M. The dorsal involuting marginal zone stiffens anisotropically during its convergent extension in the gastrula of Xenopus laevis. Development (Cambridge, England). 1995;121(10): 3131-40. PMID: 7588048
  • Montefiori D, Lefkowitz L, Keller R, Holmberg V, Sandstrom E, Phair J. Absence of a clinical correlation for complement-mediated, infection-enhancing antibodies in plasma or sera from HIV-1-infected individuals. Multicenter AIDS Cohort Study Group. AIDS (London, England). 1991;5(5): 513-7. PMID: 1863402
  • Keller R, Schwab R, Krenzelok E. Contribution of sorbitol combined with activated charcoal in prevention of salicylate absorption. Annals of emergency medicine. 1990;19(6): 654-6. PMID: 2188536