PUBLICATION

Sim1a and Arnt2 contribute to hypothalamo-spinal axon guidance by regulating Robo2 activity via a Robo3-dependent mechanism

Authors
Schweitzer, J., Löhr, H., Bonkowsky, J.L., Hübscher, K., and Driever, W.
ID
ZDB-PUB-121214-5
Date
2013
Source
Development (Cambridge, England)   140(1): 93-106 (Journal)
Registered Authors
Bonkowsky, Joshua, Driever, Wolfgang, Löhr, Heiko, Schweitzer, Jörn
Keywords
Robot/Slit signalling, Robo receptor isoforms, Dcc/Netrin signalling, dopaminergic neurons, neuroendocrine systems, hypocretinergic neurons, hypothalamo-spinal projections, orthopedia, zebrafish
MeSH Terms
  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator/genetics
  • Aryl Hydrocarbon Receptor Nuclear Translocator/physiology*
  • Basic Helix-Loop-Helix Transcription Factors/genetics
  • Basic Helix-Loop-Helix Transcription Factors/physiology*
  • Hypothalamus/embryology
  • Hypothalamus/physiology*
  • Nerve Tissue Proteins/antagonists & inhibitors
  • Nerve Tissue Proteins/genetics
  • Nerve Tissue Proteins/physiology
  • RNA Splicing/genetics
  • Receptors, Immunologic/antagonists & inhibitors*
  • Receptors, Immunologic/genetics
  • Receptors, Immunologic/metabolism*
  • Receptors, Immunologic/physiology*
  • Repressor Proteins/genetics
  • Repressor Proteins/physiology*
  • Spinal Cord/embryology
  • Spinal Cord/physiology*
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish Proteins/antagonists & inhibitors*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Zebrafish Proteins/physiology*
(all 25)
PubMed
23222439 Full text @ Development
Abstract

Precise spatiotemporal control of axon guidance factor expression is a prerequisite for formation of functional neuronal connections. Although Netrin/Dcc- and Robo/Slit-mediated attractive and repulsive guidance of commissural axons have been extensively studied, little is known about mechanisms controlling mediolateral positioning of longitudinal axons in vertebrates. Here, we use a genetic approach in zebrafish embryos to study pathfinding mechanisms of dopaminergic and neuroendocrine longitudinal axons projecting from the hypothalamus into hindbrain and spinal cord. The transcription factors Sim1a and Arnt2 contribute to differentiation of a defined population of dopaminergic and neuroendocrine neurons. We show that both factors also control aspects of axon guidance: Sim1a or Arnt2 depletion results in displacement of hypothalamo-spinal longitudinal axons towards the midline. This phenotype is suppressed in robo3 guidance receptor mutant embryos. In the absence of Sim1a and Arnt2, expression of the robo3 splice isoform robo3a.1 is increased in the hypothalamus, indicating negative control of robo3a.1 transcription by these factors. We further provide evidence that increased Robo3a.1 levels interfere with Robo2-mediated repulsive axon guidance. Finally, we show that the N-terminal domain unique to Robo3a.1 mediates the block of Robo2 repulsive activity. Therefore, Sim1a and Arnt2 contribute to control of lateral positioning of longitudinal hypothalamic-spinal axons by negative regulation of robo3a.1 expression, which in turn attenuates the repulsive activity of Robo2.

Genes / Markers
Marker Marker Type Name
arnt2GENEaryl-hydrocarbon receptor nuclear translocator 2
avpGENEarginine vasopressin
crhbGENEcorticotropin releasing hormone b
dccGENEDCC netrin 1 receptor
hcrtGENEhypocretin (orexin) neuropeptide precursor
hsp70lGENEheat shock cognate 70-kd protein, like
otpbGENEorthopedia homeobox b
oxtGENEoxytocin
robo2GENEroundabout, axon guidance receptor, homolog 2 (Drosophila)
robo3GENEroundabout, axon guidance receptor, homolog 3 (Drosophila)
1 - 10 of 17
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Figures
Figure Gallery (19 images) / 2
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hi2639cTgTransgenic Insertion
m1163TgTransgenic Insertion
    m1217TgTransgenic Insertion
      m1218TgTransgenic Insertion
        te284
          Point Mutation
          ti272z
            Point Mutation
            tw204
              MNV
              zc49TgTransgenic Insertion
                1 - 8 of 8
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                Human Disease / Model
                No data available
                Sequence Targeting Reagents
                Target Reagent Reagent Type
                arnt2MO3-arnt2MRPHLNO
                dccMO2-dccMRPHLNO
                sim1aMO2-sim1aMRPHLNO
                1 - 3 of 3
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                Fish
                Antibodies
                Orthology
                No data available
                Engineered Foreign Genes
                Marker Marker Type Name
                EGFPEFGEGFP
                TomatoEFGTomato
                1 - 2 of 2
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                Mapping
                No data available