PIONEER AXON GUIDANCE IN THE EMBRYONIC FOREBRAIN

Summary

Principal Investigator: GRANT STEPHEN MASTICK
Abstract: DESCRIPTION (From the Applicant's Abstract): The long-term objective of this application is to increase our knowledge of how the growth and guidance of axons is regulated during embryonic development. The functioning nervous system requires precise interconnections between neurons, and this application aims to dissect the guidance mechanisms of a set of axons that pioneers the first longitudinal tract in the mouse forebrain, the tract of the postoptic commissure (tpoc). This tract is foundational, as it lays down the pathway followed by a multitude of later ascending and descending axons. Therefore the tpoc is crucial to understanding the formation of neural circuitry in the basal forebrain. Recently, we discovered that the tpoc axons make severe guidance errors in embryos mutant for the transcription factor Pax6. This mutant provides an opportunity to discover how early patterning genes, such as Pax6, might provide positional information in the form of guidance cues. The main approach will be to challenge the axons by creating altered patterns of Pax6 in the developing brain. Analysis of axon responses will reveal where and how Pax6 acts to influence axon outgrowth. To alter Pax6 expression patterns, several different strategies will be used. A new electroporation method will be used to target gene expression in intact embryos, including restoration of Pax6 to local regions of Pax6 mutant embryos, expansion of Pax6 expression in wild type embryos, and interference with endogenous Pax6 by targeted expression of dominant negative alleles of Pax6. The effect of altered Pax6 expression will also be examined in chimeric embryos with a mixture of wild type and Pax6 mutant cells, and in mutant mice that selectively lack Pax6 in only one cell type. In an initial analysis of downstream targets of Pax6, the axon guidance role of the Pax6-dependent cell adhesion molecule R-cadherin will also be examined by in vitro approaches and embryo electroporation experiments. This work will contribute to our knowledge of both the normal and mutant developing nervous system. Developmental defects underlie many devastating neurological disorders, and understanding the mechanisms of axon pathfinding and neuronal patterning may eventually lead to strategies for prevention or treatment of birth defects. In addition, the mechanisms of axon growth during development may give insight into how regeneration of the nervous system may be stimulated following trauma or disease.
Funding Period: 2001-02-21 - 2007-01-31
more information: NIH RePORT

Top Publications

  1. pmc Robo1 and Robo2 have distinct roles in pioneer longitudinal axon guidance
    Minkyung Kim
    Department of Biology, University of Nevada, Reno, NV 89557, USA
    Dev Biol 358:181-8. 2011
  2. pmc Slit-Robo signals regulate pioneer axon pathfinding of the tract of the postoptic commissure in the mammalian forebrain
    Itzel Ricaño-Cornejo
    Instituto de Neurobiologia, Universidad Nacional Autonoma de Mexico, Queretaro, Mexico
    J Neurosci Res 89:1531-41. 2011
  3. pmc Midbrain dopaminergic axons are guided longitudinally through the diencephalon by Slit/Robo signals
    James P Dugan
    Department of Biology, University of Nevada, Reno, NV 89557, USA
    Mol Cell Neurosci 46:347-56. 2011
  4. pmc Longitudinal axons are guided by Slit/Robo signals from the floor plate
    Grant S Mastick
    Department of Biology, University of Nevada, Reno, NV, USA
    Cell Adh Migr 4:337-41. 2010
  5. pmc Dscam guides embryonic axons by Netrin-dependent and -independent functions
    Gracie L Andrews
    Department of Biology MS 314, University of Nevada, Reno, NV 89557, USA
    Development 135:3839-48. 2008
  6. pmc Pioneer longitudinal axons navigate using floor plate and Slit/Robo signals
    W Todd Farmer
    Department of Biology, University of Nevada, Reno, NV 89557, USA
    Development 135:3643-53. 2008
  7. pmc A dlx2- and pax6-dependent transcriptional code for periglomerular neuron specification in the adult olfactory bulb
    Monika S Brill
    Department of Physiological Genomics, Institute of Physiology, Ludwig Maximilians University Munich, D 80336 Munich, Germany
    J Neurosci 28:6439-52. 2008
  8. pmc The Slit receptor Robo1 is predominantly expressed via the Dutt1 alternative promoter in pioneer neurons in the embryonic mouse brain and spinal cord
    Hikmet Feyza Nural
    Department of Biology, University of Nevada, Reno, NV 89557, USA
    Gene Expr Patterns 7:837-45. 2007
  9. pmc Multiple requirements for Hes 1 during early eye formation
    Hae Young Lee
    Department of Pediatrics, Northwestern University Medical School at Children s Memorial Institute for Education and Research, Chicago, IL 60614, USA
    Dev Biol 284:464-78. 2005
  10. ncbi EphB receptor tyrosine kinases control morphological development of the ventral midbrain
    Amy L Altick
    Biochemistry Graduate Program, Department of Biology, University of Nevada, Mail Stop 200, Reno, NV 89557, USA
    Mech Dev 122:501-12. 2005

Scientific Experts

  • GRANT STEPHEN MASTICK
  • W Todd Farmer
  • Hikmet Feyza Nural
  • Amy L Altick
  • James P Dugan
  • Gary T Philips
  • Hae Young Lee
  • Itzel Ricaño-Cornejo
  • Minkyung Kim
  • Gracie L Andrews
  • Thomas Kidd
  • Monika S Brill
  • Frederic Charron
  • Michael A Berberoglu
  • Nadean L Brown
  • Emily Wroblewski
  • Carrie N Stair
  • Claudia M García-Peña
  • Philipe R F Mendonca
  • Hilary P Riley
  • Andrew P Roesener
  • Amaya Miquelajauregui
  • Diego Echevarria
  • Alfredo Varela-Echavarria
  • Andrea Stratton
  • Magdalena Gotz
  • Jovica Ninkovic
  • George C Fernandez
  • Ruth Ashery-Padan
  • Hilary Price
  • Benedikt Berninger
  • Armen Saghatelyan
  • Shawna Tanglao
  • Hilde Wohlfrom
  • Steven Brotman
  • Marina Snapyan
  • Steves Morin
  • Melanie Jawerka
  • Christopher Dravis
  • Meredith Reedy
  • Tracey Bowdler
  • Kevin Conley
  • Mark Henkemeyer

Detail Information

Publications11

  1. pmc Robo1 and Robo2 have distinct roles in pioneer longitudinal axon guidance
    Minkyung Kim
    Department of Biology, University of Nevada, Reno, NV 89557, USA
    Dev Biol 358:181-8. 2011
    ..Therefore, while Robo1 and 2 have some genetic overlap to cooperate in guiding longitudinal axons, each isoform has distinct functions in specific longitudinal axon populations...
  2. pmc Slit-Robo signals regulate pioneer axon pathfinding of the tract of the postoptic commissure in the mammalian forebrain
    Itzel Ricaño-Cornejo
    Instituto de Neurobiologia, Universidad Nacional Autonoma de Mexico, Queretaro, Mexico
    J Neurosci Res 89:1531-41. 2011
    ..These results reveal that Slit-Robo signaling regulates the dorsoventral position of this pioneer tract in the developing forebrain...
  3. pmc Midbrain dopaminergic axons are guided longitudinally through the diencephalon by Slit/Robo signals
    James P Dugan
    Department of Biology, University of Nevada, Reno, NV 89557, USA
    Mol Cell Neurosci 46:347-56. 2011
    ..These results indicate that Slit/Robo signaling is critical during the initial establishment of dopaminergic pathways, with roles in the dorsoventral positioning and precise pathfinding of these ascending longitudinal axons...
  4. pmc Longitudinal axons are guided by Slit/Robo signals from the floor plate
    Grant S Mastick
    Department of Biology, University of Nevada, Reno, NV, USA
    Cell Adh Migr 4:337-41. 2010
    ..These dual functions likely cooperate with other guidance cues to establish the major longitudinal tracts in the brain...
  5. pmc Dscam guides embryonic axons by Netrin-dependent and -independent functions
    Gracie L Andrews
    Department of Biology MS 314, University of Nevada, Reno, NV 89557, USA
    Development 135:3839-48. 2008
    ..These functions in axon guidance have implications for the pathogenesis of Down Syndrome...
  6. pmc Pioneer longitudinal axons navigate using floor plate and Slit/Robo signals
    W Todd Farmer
    Department of Biology, University of Nevada, Reno, NV 89557, USA
    Development 135:3643-53. 2008
    ..However, combined Robo1 and Robo2 mutations strongly disrupted each pioneer tract. Thus, pioneer axons depend on long-range floor plate cues, with Slit/Robo signaling required for precise longitudinal trajectories...
  7. pmc A dlx2- and pax6-dependent transcriptional code for periglomerular neuron specification in the adult olfactory bulb
    Monika S Brill
    Department of Physiological Genomics, Institute of Physiology, Ludwig Maximilians University Munich, D 80336 Munich, Germany
    J Neurosci 28:6439-52. 2008
    ..Thus, Dlx2 wields a dual function by first instructing generic neurogenesis from adult precursors and subsequently specifying PGN subtypes in conjunction with Pax6...
  8. pmc The Slit receptor Robo1 is predominantly expressed via the Dutt1 alternative promoter in pioneer neurons in the embryonic mouse brain and spinal cord
    Hikmet Feyza Nural
    Department of Biology, University of Nevada, Reno, NV 89557, USA
    Gene Expr Patterns 7:837-45. 2007
    ..For both probes, the main hybridization signal was limited to two spots in the nuclei of individual cells. This study shows distinct expression patterns for the Dutt1 and Robo1 alternative promoters in the embryonic nervous system...
  9. pmc Multiple requirements for Hes 1 during early eye formation
    Hae Young Lee
    Department of Pediatrics, Northwestern University Medical School at Children s Memorial Institute for Education and Research, Chicago, IL 60614, USA
    Dev Biol 284:464-78. 2005
    ..Together, these studies demonstrate that Hes1, like Pax6, simultaneously regulates multiple developmental processes during optic development...
  10. ncbi EphB receptor tyrosine kinases control morphological development of the ventral midbrain
    Amy L Altick
    Biochemistry Graduate Program, Department of Biology, University of Nevada, Mail Stop 200, Reno, NV 89557, USA
    Mech Dev 122:501-12. 2005
    ..Our data suggests a role for EphB signaling in morphological organization of specific regions of the developing neural tube...
  11. pmc Precocious retinal neurons: Pax6 controls timing of differentiation and determination of cell type
    Gary T Philips
    Biology Department, University of Nevada, Biology 200, 1664 N Virginia Street, Reno, NV 89557, USA
    Dev Biol 279:308-21. 2005
    ..Subsequently, precocious neurons adopted a generic rather than a specific retinal neuron fate. Thus, Pax6 regulates the timing of retinal neurogenesis and couples it with specific neuron differentiation programs...