DSCAM promotes axon fasciculation and growth in the developing optic pathway

Freyja M Bruce, Samantha Brown, Jonathan N Smith, Peter G Fuerst, Lynda Erskine

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14 Citations (Scopus)
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Abstract

Although many aspects of optic pathway development are beginning to be understood, the mechanisms promoting the growth of retinal ganglion cell (RGC) axons toward visual targets remain largely unknown. Down syndrome cell adhesion molecule (Dscam) is expressed by mouse RGCs shortly after they differentiate at embryonic day 12 and is essential for multiple aspects of postnatal visual system development. Here we show that Dscam is also required during embryonic development for the fasciculation and growth of RGC axons. Dscam is expressed along the developing optic pathway in a pattern consistent with a role in regulating RGC axon outgrowth. In mice carrying spontaneous mutations in Dscam (Dscamdel17; Dscam2J), RGC axons pathfind normally, but growth from the chiasm toward their targets is impaired, resulting in a delay in RGC axons reaching the dorsal thalamus compared with that seen in wild-type littermates. Conversely, Dscam gain of function results in exuberant growth into the dorsal thalamus. The growth of ipsilaterally projecting axons is particularly affected. Axon organization in the optic chiasm and tract and RGC growth cone morphologies are also altered in Dscam mutants. In vitro DSCAM promotes RGC axon growth and fasciculation, and can act independently of cell contact. In vitro and in situ DSCAM is required both in the RGC axons and in their environment for the promotion of axon outgrowth, consistent with a homotypic mode of action. These findings identify DSCAM as a permissive signal that promotes the growth and fasciculation of RGC axons, controlling the timing of when RGC axons reach their targets.
Original languageEnglish
Pages (from-to)1702-1707
Number of pages6
JournalPNAS
Volume114
Issue number7
Early online date30 Jan 2017
DOIs
Publication statusPublished - 14 Feb 2017

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Retinal Ganglion Cells
Axons
Cell Adhesion Molecules
Down Syndrome
Growth
Fasciculation
Thalamus
Axon Fasciculation
Optic Chiasm
Growth Cones
Embryonic Development
Mutation

Keywords

  • axon guidance
  • development
  • growth cone
  • optic chiasm
  • visual system

Cite this

DSCAM promotes axon fasciculation and growth in the developing optic pathway. / Bruce, Freyja M; Brown, Samantha; Smith, Jonathan N; Fuerst, Peter G; Erskine, Lynda.

In: PNAS, Vol. 114, No. 7, 14.02.2017, p. 1702-1707.

Research output: Contribution to journalArticle

Bruce, Freyja M ; Brown, Samantha ; Smith, Jonathan N ; Fuerst, Peter G ; Erskine, Lynda. / DSCAM promotes axon fasciculation and growth in the developing optic pathway. In: PNAS. 2017 ; Vol. 114, No. 7. pp. 1702-1707.
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abstract = "Although many aspects of optic pathway development are beginning to be understood, the mechanisms promoting the growth of retinal ganglion cell (RGC) axons toward visual targets remain largely unknown. Down syndrome cell adhesion molecule (Dscam) is expressed by mouse RGCs shortly after they differentiate at embryonic day 12 and is essential for multiple aspects of postnatal visual system development. Here we show that Dscam is also required during embryonic development for the fasciculation and growth of RGC axons. Dscam is expressed along the developing optic pathway in a pattern consistent with a role in regulating RGC axon outgrowth. In mice carrying spontaneous mutations in Dscam (Dscamdel17; Dscam2J), RGC axons pathfind normally, but growth from the chiasm toward their targets is impaired, resulting in a delay in RGC axons reaching the dorsal thalamus compared with that seen in wild-type littermates. Conversely, Dscam gain of function results in exuberant growth into the dorsal thalamus. The growth of ipsilaterally projecting axons is particularly affected. Axon organization in the optic chiasm and tract and RGC growth cone morphologies are also altered in Dscam mutants. In vitro DSCAM promotes RGC axon growth and fasciculation, and can act independently of cell contact. In vitro and in situ DSCAM is required both in the RGC axons and in their environment for the promotion of axon outgrowth, consistent with a homotypic mode of action. These findings identify DSCAM as a permissive signal that promotes the growth and fasciculation of RGC axons, controlling the timing of when RGC axons reach their targets.",
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N1 - Acknowledgments We thank Drs. Robert Burgess, Carol Mason, and Eloisa Herrera for helpful discussions; Dr. Thomas Theil for his invaluable advice on the slice culture methods; Francesca Lamb and Emma Smith for technical assistance; and the Institute of Medical Sciences Microscopy and Imaging Facility for assistance with confocal microscopy. This work was supported by a Biotechnology and Biological Sciences Research Council (BBSRC) doctoral training award studentship and a BBSRC project grant (BB/J00815X/1). Freely available online through the PNAS open access option.

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N2 - Although many aspects of optic pathway development are beginning to be understood, the mechanisms promoting the growth of retinal ganglion cell (RGC) axons toward visual targets remain largely unknown. Down syndrome cell adhesion molecule (Dscam) is expressed by mouse RGCs shortly after they differentiate at embryonic day 12 and is essential for multiple aspects of postnatal visual system development. Here we show that Dscam is also required during embryonic development for the fasciculation and growth of RGC axons. Dscam is expressed along the developing optic pathway in a pattern consistent with a role in regulating RGC axon outgrowth. In mice carrying spontaneous mutations in Dscam (Dscamdel17; Dscam2J), RGC axons pathfind normally, but growth from the chiasm toward their targets is impaired, resulting in a delay in RGC axons reaching the dorsal thalamus compared with that seen in wild-type littermates. Conversely, Dscam gain of function results in exuberant growth into the dorsal thalamus. The growth of ipsilaterally projecting axons is particularly affected. Axon organization in the optic chiasm and tract and RGC growth cone morphologies are also altered in Dscam mutants. In vitro DSCAM promotes RGC axon growth and fasciculation, and can act independently of cell contact. In vitro and in situ DSCAM is required both in the RGC axons and in their environment for the promotion of axon outgrowth, consistent with a homotypic mode of action. These findings identify DSCAM as a permissive signal that promotes the growth and fasciculation of RGC axons, controlling the timing of when RGC axons reach their targets.

AB - Although many aspects of optic pathway development are beginning to be understood, the mechanisms promoting the growth of retinal ganglion cell (RGC) axons toward visual targets remain largely unknown. Down syndrome cell adhesion molecule (Dscam) is expressed by mouse RGCs shortly after they differentiate at embryonic day 12 and is essential for multiple aspects of postnatal visual system development. Here we show that Dscam is also required during embryonic development for the fasciculation and growth of RGC axons. Dscam is expressed along the developing optic pathway in a pattern consistent with a role in regulating RGC axon outgrowth. In mice carrying spontaneous mutations in Dscam (Dscamdel17; Dscam2J), RGC axons pathfind normally, but growth from the chiasm toward their targets is impaired, resulting in a delay in RGC axons reaching the dorsal thalamus compared with that seen in wild-type littermates. Conversely, Dscam gain of function results in exuberant growth into the dorsal thalamus. The growth of ipsilaterally projecting axons is particularly affected. Axon organization in the optic chiasm and tract and RGC growth cone morphologies are also altered in Dscam mutants. In vitro DSCAM promotes RGC axon growth and fasciculation, and can act independently of cell contact. In vitro and in situ DSCAM is required both in the RGC axons and in their environment for the promotion of axon outgrowth, consistent with a homotypic mode of action. These findings identify DSCAM as a permissive signal that promotes the growth and fasciculation of RGC axons, controlling the timing of when RGC axons reach their targets.

KW - axon guidance

KW - development

KW - growth cone

KW - optic chiasm

KW - visual system

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DO - 10.1073/pnas.1618606114

M3 - Article

VL - 114

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EP - 1707

JO - PNAS

JF - PNAS

SN - 0027-8424

IS - 7

ER -