Scott Holley, PhD
Research & Publications
We use zebrafish as a model system to understand human development and the etiology of human disease. We study somitogenesis which is the process of creating the precursors to the vertebral column and musculature during embryogenesis. Aberrations in this process lead to a birth defect called spondylocostal dysostosis in humans. In addition, we study the mechanism of body elongation. Our research utilizes genetics, molecular biology, advanced imaging, quantitative image analysis and computational modeling. Ultimately, we want to understand how the combined interactions between genes, cells and cellular mechanics facilitate the emergence of higher levels of organization in embryonic development and tissue homeostasis.
Extensive Research Description
The physical characteristics of the cellular environment influence cell differentiation, and reciprocally, cell differentiation often manifests as alterations in adhesion, rigidity and motility. Some of the most rapid and interdependent changes in both physical form and cell differentiation occur during embryonic development. However, we still have a poorly integrated understanding of the relationships between genetic control and the physical characteristics of tissues.
The tailbud is the posterior leading edge of the growing vertebrate embryo consisting of motile progenitors of the axial skeleton, musculature and spinal cord. In a recent study, we measured the 3-D cell flow field of the zebrafish tailbud and identified changes in tissue fluidity revealed by reductions in the coherence of cell motion without alteration of cell velocities. We found a directed posterior flow wherein the polarization between individual cell motion is high reflecting ordered collective migration. At the posterior tip of the tailbud, this flow makes sharp bilateral turns facilitated by with extensive cell mixing due to increased directional variability of individual cell motions. Genetic perturbation of cell signaling or cell adhesion reduces the coherence of the flow but has different consequence for trunk and tail extension. Interplay between the coherence and rate of cell flow determines whether congestion forms within the flow and the body axis becomes contorted. Future studies will build upon this systems understanding of tissue fluidity within the tailbud by incorporating additional signaling pathways and cell-extracellular matrix interactions, cell-cell adhesion as well as developing more accurate computer models of the cell flow. We are also studying the physical forces within tailbud and the reciprocal relationships between genetic control the physical properties of the cellular and tissue environment. These studies will increase understanding of how a tissue’s physical characteristics impacts morphogenesis, tissue homeostasis and disease in humans.
Biomechanical Phenomena; Genetics; Zebrafish; Developmental Biology; Organogenesis; Systems Biology
- Integrin intra-heterodimer affinity inversely correlates with integrin activatabilitySun G, Guillon E, Holley SA. Integrin intra-heterodimer affinity inversely correlates with integrin activatability Cell Reports 2021, 35: 109230. PMID: 34107244, PMCID: PMC8227800, DOI: 10.1016/j.celrep.2021.109230.
- Fibronectin is a smart adhesive that both influences and responds to the mechanics of early spinal column developmentGuillon E, Das D, Jülich D, Hassan AR, Geller H, Holley S. Fibronectin is a smart adhesive that both influences and responds to the mechanics of early spinal column development ELife 2020, 9: e48964. PMID: 32228864, PMCID: PMC7108867, DOI: 10.7554/elife.48964.
- Organization of Embryonic Morphogenesis via Mechanical InformationDas D, Jülich D, Schwendinger-Schreck J, Guillon E, Lawton AK, Dray N, Emonet T, O'Hern CS, Shattuck MD, Holley SA. Organization of Embryonic Morphogenesis via Mechanical Information Developmental Cell 2019, 49: 829-839.e5. PMID: 31178400, PMCID: PMC6590525, DOI: 10.1016/j.devcel.2019.05.014.
- Patterned Disordered Cell Motion Ensures Vertebral Column SymmetryDas D, Chatti V, Emonet T, Holley SA. Patterned Disordered Cell Motion Ensures Vertebral Column Symmetry Developmental Cell 2017, 42: 170-180.e5. PMID: 28743003, PMCID: PMC5568629, DOI: 10.1016/j.devcel.2017.06.020.
- Cross-Scale Integrin Regulation Organizes ECM and Tissue TopologyJülich D, Cobb G, Melo AM, McMillen P, Lawton AK, Mochrie SG, Rhoades E, Holley SA. Cross-Scale Integrin Regulation Organizes ECM and Tissue Topology Developmental Cell 2015, 34: 33-44. PMID: 26096733, PMCID: PMC4496283, DOI: 10.1016/j.devcel.2015.05.005.
- A Sawtooth Pattern of Cadherin 2 Stability Mechanically Regulates Somite MorphogenesisMcMillen P, Chatti V, Jülich D, Holley SA. A Sawtooth Pattern of Cadherin 2 Stability Mechanically Regulates Somite Morphogenesis Current Biology 2016, 26: 542-549. PMID: 26853361, PMCID: PMC4822709, DOI: 10.1016/j.cub.2015.12.055.
- Cell-Fibronectin Interactions Propel Vertebrate Trunk Elongation via Tissue MechanicsDray N, Lawton A, Nandi A, Jülich D, Emonet T, Holley SA. Cell-Fibronectin Interactions Propel Vertebrate Trunk Elongation via Tissue Mechanics Current Biology 2013, 23: 1335-1341. PMID: 23810535, PMCID: PMC3725194, DOI: 10.1016/j.cub.2013.05.052.
- Regulated tissue fluidity steers zebrafish body elongationLawton AK, Nandi A, Stulberg MJ, Dray N, Sneddon MW, Pontius W, Emonet T, Holley SA. Regulated tissue fluidity steers zebrafish body elongation Development 2013, 140: 573-582. PMID: 23293289, PMCID: PMC3561786, DOI: 10.1242/dev.090381.
- Crosstalk between Fgf and Wnt signaling in the zebrafish tailbudStulberg MJ, Lin A, Zhao H, Holley SA. Crosstalk between Fgf and Wnt signaling in the zebrafish tailbud Developmental Biology 2012, 369: 298-307. PMID: 22796649, PMCID: PMC3423502, DOI: 10.1016/j.ydbio.2012.07.003.
- The Her7 node modulates the network topology of the zebrafish segmentation clock via sequestration of the Hes6 hubTrofka A, Schwendinger-Schreck J, Brend T, Pontius W, Emonet T, Holley SA. The Her7 node modulates the network topology of the zebrafish segmentation clock via sequestration of the Hes6 hub Development 2012, 139: 940-947. PMID: 22278920, PMCID: PMC3274355, DOI: 10.1242/dev.073544.
- Essential roles of fibronectin in the development of the left–right embryonic body planPulina M, Hou S, Mittal A, Julich D, Holley S, Hynes R, Astrof S. Essential roles of fibronectin in the development of the left–right embryonic body plan Developmental Biology 2011, 356: 152. DOI: 10.1016/j.ydbio.2011.05.178.
- Control of extracellular matrix assembly along tissue boundaries via Integrin and Eph/Ephrin signalingJülich D, Mould AP, Koper E, Holley SA. Control of extracellular matrix assembly along tissue boundaries via Integrin and Eph/Ephrin signaling Development 2009, 136: 2913-2921. PMID: 19641014, DOI: 10.1242/dev.038935.
- Generation and interpretation of segmentation clock pattern during zebrafish somitogenesisHolley S. Generation and interpretation of segmentation clock pattern during zebrafish somitogenesis Developmental Biology 2009, 331: 397. DOI: 10.1016/j.ydbio.2009.05.046.
- Segmentation of touching cell nuclei using gradient flow trackingLI G, LIU T, NIE J, GUO L, CHEN J, ZHU J, XIA W, MARA A, HOLLEY S, WONG S. Segmentation of touching cell nuclei using gradient flow tracking Journal Of Microscopy 2008, 231: 47-58. PMID: 18638189, DOI: 10.1111/j.1365-2818.2008.02016.x.
- beamter/deltaC and the role of Notch ligands in the zebrafish somite segmentation, hindbrain neurogenesis and hypochord differentiationJülich D, Lim C, Round J, Nicolaije C, Schroeder J, Davies A, Geisler R, Lewis J, Jiang Y, Holley S, Consortium T. beamter/deltaC and the role of Notch ligands in the zebrafish somite segmentation, hindbrain neurogenesis and hypochord differentiation Developmental Biology 2005, 286: 391-404. PMID: 16125692, DOI: 10.1016/j.ydbio.2005.06.040.
- Integrinα5 and Delta/Notch Signaling Have Complementary Spatiotemporal Requirements during Zebrafish SomitogenesisJu¨lich D, Geisler R, Consortium T, Holley S. Integrinα5 and Delta/Notch Signaling Have Complementary Spatiotemporal Requirements during Zebrafish Somitogenesis Developmental Cell 2005, 8: 575-586. PMID: 15809039, DOI: 10.1016/j.devcel.2005.01.016.
- Control of her1 expression during zebrafish somitogenesis by a Delta-dependent oscillator and an independent wave-front activityHolley S, Geisler R, Nüsslein-Volhard C. Control of her1 expression during zebrafish somitogenesis by a Delta-dependent oscillator and an independent wave-front activity Genes & Development 2000, 14: 1678-1690. PMID: 10887161, PMCID: PMC316735, DOI: 10.1101/gad.14.13.1678.
- A radiation hybrid map of the zebrafish genomeGeisler R, Rauch G, Baier H, van Bebber F, Broβ L, Dekens M, Finger K, Fricke C, Gates M, Geiger H, Geiger-Rudolph S, Gilmour D, Glaser S, Gnügge L, Habeck H, Hingst K, Holley S, Keenan J, Kirn A, Knaut H, Lashkari D, Maderspacher F, Martyn U, Neuhauss S, Neumann C, Nicolson T, Pelegri F, Ray R, Rick J, Roehl H, Roeser T, Schauerte H, Schier A, Schönberger U, Schönthaler H, Schulte-Merker S, Seydler C, Talbot W, Weiler C, Nüsslein-Volhard C, Haffter P. A radiation hybrid map of the zebrafish genome Nature Genetics 1999, 23: 86-89. PMID: 10471505, DOI: 10.1038/12692.
- 8 Somitogenesis in ZebrafishHolley S, Nüsslein-Volhard C. 8 Somitogenesis in Zebrafish 1999, 47: 247-277. PMID: 10595307, DOI: 10.1016/s0070-2153(08)60727-9.
- Zebrafish segmentation and pair‐rule patterningvan Eeden F, Holley S, Haffter P, Nüsslein‐Volhard C. Zebrafish segmentation and pair‐rule patterning Genesis 1998, 23: 65-76. PMID: 9706695, DOI: 10.1002/(sici)1520-6408(1998)23:1<65::aid-dvg7>3.0.co;2-4.