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Ryan Range, Ph.D.

Postdoctoral Fellow
Developmental Mechanisms Section

NATIONAL INSTITUTES OF HEALTH/NIDCR
BUILDING 30, ROOM 523
30 CONVENT DRIVE MSC 4326
BETHESDA, MD 20892

Phone: 301-496-1392
Fax: 301-480-5353
E-mail: rangery@mail.nih.gov

Biographical Sketch

I received a B.A. in 1997 from the University of Texas at Austin studying biology. In 2005, I received a Ph.D. from the Department of Cellular and Molecular Biology at Duke University where I conducted research on the regulation of the Notch and Wnt signaling pathways during early endomesoderm specification in the sea urchin embryo. These studies lead to a better understanding of the how the endomesoderm gene regulatory network is initially activated and to the discovery of a novel mechanism for the post-translational regulation of Notch signaling. As a post-doctoral fellow in the laboratory of Thierry Lepage at the Observatiore Oceanologique/ University of Paris 6 in Villefranche-sur-Mer, France, I studied the regulatory mechanisms controlling expression of nodal, which is necessary and sufficient for dorsal-ventral axis specification. These studies led to the discovery of a maternal regulatory network that is essential for nodal’s activation and dorsal-ventral axis specification. I moved to the NIH for a second post-doc in the Angerer lab in order to study the earliest signal transduction pathways used by sea urchin embryos to activate the gene regulatory programs necessary to establish and pattern the neuroectoderm along the primary, anterior-posterior (AP) axis.

Research Interests/Scientific Focus

Patterning of the neuroectoderm in sea urchin embryos - click to enlarge

Patterning of the anterior neuroectoderm in sea urchin embryos
(Click on image to enlarge.)

Embryonic axes form the backbone of the animal body plan therefore one of the key questions in biology is to understand how developmental regulatory programs pattern embryos along the major axes. The sea urchin embryo is an excellent model system for these studies because its relative simplicity allows us to understand early cell specification events that are obscured by the complexity of overlapping signaling events and complex cell movements in vertebrates. Moreover, sea urchins belong to the most basal deuterostome phylum, making them an excellent model to understand the evolution of both chordate and protostome embryos. This is important, because, in order to understand the evolution of developmental regulatory programs, we need to construct programs from a diverse group of model systems. For example, over the past decade studies in such invertebrate embryos as cnidarians, spiders, and hemichordates, have provided convincing new evidence that early posterior Wnt/ß-catenin signaling establishes AP polarity in bilaterians. Similarly, it is well established in sea urchin embryos that early, graded Wnt/ß-catenin signaling at the posterior pole of the embryo specifies and patterns the endoderm and mesoderm along this axis. In the vertebrates, Wnt/ß-catenin is essential for establishing AP polarity early in development, but it is also used later to pattern the neuroectoderm along the AP axis during pre-gastrula and gastrula stages. It is not known when this later mechanism evolved. Recently, the Angerer lab used high throughput genome-wide assays to monitor the effects of gene perturbation in urchin embryos and showed that, remarkably, the anterior neuroectoderm (ANE) of the sea urchin embryo expresses a large number of orthologues of vertebrate forebrain/eye-field factors. Interestingly, in both vertebrate and sea urchin embryos the early neuroectoderm is patterned along the AP axis by a molecular mechanism(s) that relies on posterior Wnt/ß-catenin signaling. These data suggest that the sea urchin ANE may represent the ancient gene regulatory network upon which the more elaborate vertebrate forebrain/eye-field was created and that these two territories may be patterned by similar developmental processes.

My recent research focuses on several Wnt signaling pathway members and modulators in an attempt to more clearly define the developmental mechanism(s) used to pattern the neuroectoderm along the urchin AP axis. The data strongly suggest ANE centralization and subsequent regionalization occurs in at least 4 steps that depend on the integration of information from at least 3 different Wnt signaling pathways and several Wnt signaling modulators.

  • In the first step (16- to 32-cell stage), the expression patterns of the earliest neuro-ectoderm genes, six3 and foxq2, indicate that the neuroectoderm regulatory state is initially broadly activated throughout the anterior half of the 32-cell embryo. Wnt/ß-catenin signaling prevents neural specification in the posterior half of the embryo (endomesoderm), since the entire embryo expresses early ANE factors and subsequently turns into a neuroepithelial ball when ß-catenin nuclearization is inhibited (Fig. 1A). These results suggest that neuroectoderm fate is initially specified by ubiquitous maternal factors.
  • In the second step (60-cell to late blastula stage), posterior Wnt/ß-catenin signaling activates expression of two Wnt ligands, Wnt1 and Wnt8, which signal through the Frizzled5/8 receptor (Fzl5/8). This receptor activates the Wnt/Jnk signaling pathway, resulting in the down regulation of ANE factors in the posterior ectoderm (the cells between posterior endomesoderm cells and the ANE) (Fig. 1B). In a surprising finding, another Frizzled receptor, Fzl1/2/7, signaling through an unknown pathway antagonizes both the Wnt/ß-catenin and the Wnt/Fzl5/8/Jnk signaling pathways, which prevents them from eliminating ANE specification at the anterior pole (Fig. 1A, C).
  • In the third step (late blastula stage), Fzl5/8 signaling at the anterior pole activates Dkk1 expression right before gastrulation, exactly when ANE restriction is in its terminal stages. In an interesting temporal negative feedback circuit, later Fzl5/8 signaling activates Dkk1which then prevents Fzl5/8 signaling from down regulating ANE factors at the anterior pole, thereby defining the outer borders of the ANE territory (Fig. 1C).
  • Finally, in the last step (gastrula stages), the Dkk1-stabilized ANE territory is further regionalized into an outer ring and a central disk of cells. Gain- and loss-of-function studies strongly suggest that negative regulatory interactions between at least two Wnt modulators, sFrp1/5 and Dkk3, are essential for this final patterning (Fig.1D).

Selected Publications

  1. Range RC, Angerer RC, and Angerer, LA. “Complex control of Wnt signaling along the anterior-posterior axis centralizes the anterior neuroectoderm of the sea urchin embryo”. Submitted to Cell/Developmental Cell. 2011.
  2. Wei Z, Range R, Angerer R, and Angerer L. “Axial patterning interactions in the sea urchin embryo: the suppression of nodal by Wnt1 signaling”. In revision. Development. 2011.
  3. Sethi AJ, Wikramanayake RM, Angerer RC, Range RC, and Angerer LA. “Endomesoderm segregation through signaling crosstalk between gene regulatory circuits”. In revision. Science. 2011.
  4. Range R and Lepage T. “Maternal Oct1/2 is required for Nodal and Vg1/Univin expression during dorsal-ventral axis specification in the sea urchin embryo”. Developmental Biology. 2011; 17(10): 1487-98.
  5. Croce J, Range R, Wu S, Miranda E, Lhomond G, Chieh-fu Peng J, Lepage T and McClay, DR. “Wnt 6 activates endoderm in the sea urchin gene regulatory network”. Development. 2011; 138: 3297-3306.
  6. Saudemont A, Haillot E, Mekpoh F, Bessodes N, Quirin M, Lapraz F, Duboc V, Röttinger E, Range R, Oisel A, Besnardeau L, Wincker P, and Lepage T. “Gene regulatory network analysis of ectoderm specification in an echinoderm reveals ancestral regulatory circuits regulating mouth formation and neural induction”. PLoS Genetics. 2010. 6(12): e1001259.
  7. Range RC, Glenn TD, Miranda E and McClay, DR. “LvNumb works synergistically with Notch signaling to specify non-skeletal mesoderm cells in the sea urchin embryo”. Development. 2008; 135(14): 2445-54. [Featured on cover]
  8. Range R, Lapraz F, Quirin M, Marro S, Besnardeau L, Lepage T. Cis-regulatory analysis of nodal and maternal control of dorsal-ventral axis formation by Univin, a TGF-beta related to Vg1”. Development. 2007; 134(20): 3649-64.
  9. Lapraz F, Röttinger E, Duboc V, Range R, Duloquin L, Walton K, Wu SY, Bradham C, Loza MA, Hibino T, Wilson K, Poustka A, McClay D, Angerer L, Gache C, Lepage T. “RTK and TGF-beta signaling pathways genes in the sea urchin genome”. Developmental Biology. 2006; 300(1): 132-52.
  10. Sea Urchin Genome Sequencing Consortium. “The genome of the sea urchin Strongylocentrotus purpuratus”. Science. 2006; 314(5801): 941-52. [Featured on cover]
  11. Range RC, Venuti JM, and McClay, DR. “LvGroucho and nuclear b-catenin functionally compete for Tcf binding to influence activation of the endomesoderm gene regulatory network in the sea urchin embryo”. Developmental Biology. 2005; 279(1): 252-67.
  12. McClay DR, Peterson RE, Range RC, Winter-Vann AM, Ferkowicz MJ. “A micromere induction signal is activated by beta-catenin and acts through notch to initiate specification of secondary mesenchyme cells in the sea urchin embryo”. Development. 2000; 127(23): 5113-22.

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This page last updated: May 28, 2014