GENETIC MECHANISMS OF HINDBRAIN SEGMENTATION

Summary

Principal Investigator: Cecilia B Moens
Abstract: The formation of boundaries between or within tissues is a fundamental aspect of animal development. Boundaries function to separate populations of cells with different identities, allowing them to follow independent developmental programs in spite of their close proximity. Additionally, boundaries can form important organizing centers that pattern adjacent cells. In the developing vertebrate central nervous system, boundaries form in an apparently homogeneous neuroepithelium, separating brain regions that subsequently acquire distinct histological and functional properties. In the hindbrain in particular, boundaries form between the rhombomeres, producing a series of 7 segments along the main body axis. In spite of the fundamental importance of boundaries in animal development, surprisingly little is known about the molecules and mechanisms that control boundary formation. Even in Drosophila, where compartment boundaries have intrigued researchers for decades, the actual molecules that mediate boundary formation have only recently begun to be elucidated. The long-term goal of the proposed research is to understand the cellular and molecular basis of rhombomere boundary formation and maintenance during vertebrate hindbrain development. We understand that the appearance of a sharp developmental boundary involves 2 steps: first, long-range signals establish broad domains with distinct regional identities but diffuse boundaries, and secondly fine-scale interactions between cells at the edges of these domains result in the sharpening of the boundaries. In Aims 1 and 2 of this proposal we investigate the mechanisms underlying rhombomere boundary sharpening by studying two parallel processes: cell sorting, whereby cells on the "wrong" side of a forming boundary move to the "right" side, and cell plasticity, whereby cells on the "wrong" side change their identity to match that of their surroundings. Aim 1 addresses the mechanism of cell sorting, and tests the hypothesis that sorting occurs in response to 2 parallel influences: cell-cell repulsion between unlike cells at rhombomere boundaries, and cell-cell adhesion between like cells within rhombomeres. Aim 2 addresses the mechanism of plasticity. Finally, in Aim 3, we consider the mechanism by which long-range signals interact to specify the positions of specific hindbrain boundaries.
Funding Period: 2005-06-01 - 2010-05-31
more information: NIH RePORT

Top Publications

  1. pmc Hoxb1b controls oriented cell division, cell shape and microtubule dynamics in neural tube morphogenesis
    Mihaela Zigman
    Centre for Organismal Studies COS, University of Heidelberg, Im Neuenheimer Feld 329, 69120 Heidelberg, Germany
    Development 141:639-49. 2014
  2. pmc Cerebellar development in the absence of Gbx function in zebrafish
    Chen Ying Su
    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Dev Biol 386:181-90. 2014
  3. pmc RNA-seq-based mapping and candidate identification of mutations from forward genetic screens
    Adam C Miller
    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
    Genome Res 23:679-86. 2013
  4. pmc The ciliopathy gene cc2d2a controls zebrafish photoreceptor outer segment development through a role in Rab8-dependent vesicle trafficking
    Ruxandra Bachmann-Gagescu
    HHMI and Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 1024, USA
    Hum Mol Genet 20:4041-55. 2011
  5. pmc Planar polarity pathway and Nance-Horan syndrome-like 1b have essential cell-autonomous functions in neuronal migration
    Gregory S Walsh
    Howard Hughes Medical Institute and Division of Basic Science, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA
    Development 138:3033-42. 2011
  6. pmc Zebrafish Prickle1b mediates facial branchiomotor neuron migration via a farnesylation-dependent nuclear activity
    Oni M Mapp
    Committee on Developmental Biology, University of Chicago, Chicago, IL 60615, USA
    Development 138:2121-32. 2011
  7. ncbi Zebrafish neural tube morphogenesis requires Scribble-dependent oriented cell divisions
    Mihaela Zigman
    Howard Hughes Medical Institute and Division of Basic Science, Fred Hutchinson Cancer Research Center, B2 152, 1100 Fairview Avenue North, Seattle, WA 98109, USA
    Curr Biol 21:79-86. 2011
  8. pmc The neuroepithelial basement membrane serves as a boundary and a substrate for neuron migration in the zebrafish hindbrain
    Paul K Grant
    HHMI and Division of Basic Science, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109 1024, USA
    Neural Dev 5:9. 2010
  9. pmc Dhrs3a regulates retinoic acid biosynthesis through a feedback inhibition mechanism
    L Feng
    Division of Basic Science and HHMI, Fred Hutchinson Cancer Research Center, B2 152, 1100 Fairview Ave N, Seattle, WA 98109, USA
    Dev Biol 338:1-14. 2010
  10. pmc EphA4 and EfnB2a maintain rhombomere coherence by independently regulating intercalation of progenitor cells in the zebrafish neural keel
    Hilary A Kemp
    Howard Hughes Medical Institute and Division of Basic Science, Fred Hutchinson Cancer Research Center, B2 152, 1100 Fairview Ave N, Seattle, WA 98109, P O Box 19024, USA
    Dev Biol 327:313-26. 2009

Scientific Experts

  • Cecilia B Moens
  • Mihaela Zigman
  • Ruxandra Bachmann-Gagescu
  • Paul K Grant
  • Hilary A Kemp
  • Gregory S Walsh
  • Julie E Cooke
  • Chen Ying Su
  • Hung Hsiang Yu
  • Adam C Miller
  • Oni M Mapp
  • L Feng
  • Yung Shu Kuan
  • Rafael E Hernandez
  • Timothy Erickson
  • Kimberly L Cooper
  • Sean G Megason
  • Nikolaus D Obholzer
  • Arish N Shah
  • Victoria E Prince
  • John A Morgan
  • Masazumi Tada
  • D Yelon
  • R E Hernandez
  • J S Waxman
  • Andrew Jan Waskiewicz
  • Michael Brand
  • Jonathan P Myers
  • Steffen Scholpp
  • Aaron P Putzke
  • Marnie E Halpern
  • Lilyana Margaretha
  • Juli Armstrong

Detail Information

Publications18

  1. pmc Hoxb1b controls oriented cell division, cell shape and microtubule dynamics in neural tube morphogenesis
    Mihaela Zigman
    Centre for Organismal Studies COS, University of Heidelberg, Im Neuenheimer Feld 329, 69120 Heidelberg, Germany
    Development 141:639-49. 2014
    ..We propose that Hox genes can influence global tissue morphogenesis by control of microtubule dynamics in individual cells in vivo. ..
  2. pmc Cerebellar development in the absence of Gbx function in zebrafish
    Chen Ying Su
    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Dev Biol 386:181-90. 2014
    ..Based on our findings we propose a revised model for the role of Gbx in cerebellar development. ..
  3. pmc RNA-seq-based mapping and candidate identification of mutations from forward genetic screens
    Adam C Miller
    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
    Genome Res 23:679-86. 2013
    ..Overall, we show that RNA-seq is a fast, reliable, and cost-effective method to map and identify mutations that will greatly facilitate the power of forward genetics in vertebrate models...
  4. pmc The ciliopathy gene cc2d2a controls zebrafish photoreceptor outer segment development through a role in Rab8-dependent vesicle trafficking
    Ruxandra Bachmann-Gagescu
    HHMI and Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 1024, USA
    Hum Mol Genet 20:4041-55. 2011
    ..Our data support a model where Cc2d2a, localized at the photoreceptor connecting cilium/transition zone, facilitates protein transport through a role in Rab8-dependent vesicle trafficking and fusion...
  5. pmc Planar polarity pathway and Nance-Horan syndrome-like 1b have essential cell-autonomous functions in neuronal migration
    Gregory S Walsh
    Howard Hughes Medical Institute and Division of Basic Science, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA
    Development 138:3033-42. 2011
    ..These results define a role for Nhsl1b as a neuronal effector of PCP signaling and indicate that proper FBM neuron migration is directly controlled by PCP signaling between the epithelium and the migrating neurons...
  6. pmc Zebrafish Prickle1b mediates facial branchiomotor neuron migration via a farnesylation-dependent nuclear activity
    Oni M Mapp
    Committee on Developmental Biology, University of Chicago, Chicago, IL 60615, USA
    Development 138:2121-32. 2011
    ..We conclude that farnesylation-dependent nuclear localization of Pk1b is required to regulate REST localization and thus FBMN migration...
  7. ncbi Zebrafish neural tube morphogenesis requires Scribble-dependent oriented cell divisions
    Mihaela Zigman
    Howard Hughes Medical Institute and Division of Basic Science, Fred Hutchinson Cancer Research Center, B2 152, 1100 Fairview Avenue North, Seattle, WA 98109, USA
    Curr Biol 21:79-86. 2011
    ....
  8. pmc The neuroepithelial basement membrane serves as a boundary and a substrate for neuron migration in the zebrafish hindbrain
    Paul K Grant
    HHMI and Division of Basic Science, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109 1024, USA
    Neural Dev 5:9. 2010
    ..Here we examine the role of the PAR-aPKC complex in forming the basal structures that guide facial branchiomotor neurons on an appropriate migratory path...
  9. pmc Dhrs3a regulates retinoic acid biosynthesis through a feedback inhibition mechanism
    L Feng
    Division of Basic Science and HHMI, Fred Hutchinson Cancer Research Center, B2 152, 1100 Fairview Ave N, Seattle, WA 98109, USA
    Dev Biol 338:1-14. 2010
    ..Dhrs3a is thus an RA-induced feedback inhibitor of RA biosynthesis. We conclude that retinaldehyde availability is an important level at which RA biosynthesis is regulated in vertebrate embryos...
  10. pmc EphA4 and EfnB2a maintain rhombomere coherence by independently regulating intercalation of progenitor cells in the zebrafish neural keel
    Hilary A Kemp
    Howard Hughes Medical Institute and Division of Basic Science, Fred Hutchinson Cancer Research Center, B2 152, 1100 Fairview Ave N, Seattle, WA 98109, P O Box 19024, USA
    Dev Biol 327:313-26. 2009
    ..We propose a model in which Eph and Efn-dependent cell affinity within rhombomeres serve to maintain rhombomere organization during the potentially disruptive process of teleost neurulation...
  11. ncbi Neuropilin asymmetry mediates a left-right difference in habenular connectivity
    Yung Shu Kuan
    Carnegie Institution of Washington, Department of Embryology, 3520 San Martin Drive, Baltimore, MD 21218, USA
    Development 134:857-65. 2007
    ..The results indicate that Sema3D acts in concert with Nrp1a to guide neurons on the left side of the brain to innervate the target nucleus differently than those on the right side...
  12. pmc Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development
    Rafael E Hernandez
    HHMI and Division of Basic Science, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109 1024, USA
    Development 134:177-87. 2007
    ..We present a ;gradient-free' model for hindbrain patterning in which differential RA responsiveness along the hindbrain anterior-posterior axis is shaped primarily by the dynamic expression of RA-degrading enzymes...
  13. pmc Pbx proteins cooperate with Engrailed to pattern the midbrain-hindbrain and diencephalic-mesencephalic boundaries
    Timothy Erickson
    Department of Biological Sciences, CW405, Biological Sciences Building, University of Alberta, Edmonton AB, Canada T6G2E9
    Dev Biol 301:504-17. 2007
    ..Our data support a novel model of midbrain development in which Pbx and Engrailed proteins cooperatively pattern the mesencephalic region of the neural tube...
  14. ncbi Hox cofactors in vertebrate development
    Cecilia B Moens
    Division of Basic Science and HHMI, Fred Hutchinson Cancer Research Center, Seattle, WA 98115, USA
    Dev Biol 291:193-206. 2006
    ....
  15. pmc Zebrafish foggy/spt 5 is required for migration of facial branchiomotor neurons but not for their survival
    Kimberly L Cooper
    HHMI, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
    Dev Dyn 234:651-8. 2005
    ..This work provides evidence that transcript elongation is not a global mechanism equivalently required by all loci and may actually be under more strict developmental regulation...
  16. ncbi Semaphorin signaling guides cranial neural crest cell migration in zebrafish
    Hung Hsiang Yu
    Howard Hughes Medical Institute and Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Dev Biol 280:373-85. 2005
    ....
  17. ncbi EphA4 is required for cell adhesion and rhombomere-boundary formation in the zebrafish
    Julie E Cooke
    Howard Hughes Medical Institute and Division of Basic Science, Fred Hutchinson Cancer Research Center B2 152, 1100 Fairview Avenue N, P O Box 19024, Seattle, Washington 98109, USA
    Curr Biol 15:536-42. 2005
    ....