A tug of war between DCC and ROBO1 signaling during commissural axon guidance

Brianna Dailey-Krempel; Andrew L. Martin; Ha Neul Jo; Harald J. Junge; Zhe Chen

doi:10.1016/j.celrep.2023.112455

A tug of war between DCC and ROBO1 signaling during commissural axon guidance

Brianna Dailey-Krempel, Andrew L. Martin, Ha Neul Jo, Harald J. Junge, Zhe Chen

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Abstract

Dynamic and coordinated axonal responses to changing environments are critical for establishing neural connections. As commissural axons migrate across the CNS midline, they are suggested to switch from being attracted to being repelled in order to approach and to subsequently leave the midline. A molecular mechanism that is hypothesized to underlie this switch in axonal responses is the silencing of Netrin1/Deleted in Colorectal Carcinoma (DCC)-mediated attraction by the repulsive SLIT/ROBO1 signaling. Using in vivo approaches including CRISPR-Cas9-engineered mouse models of distinct Dcc splice isoforms, we show here that commissural axons maintain responsiveness to both Netrin and SLIT during midline crossing, although likely at quantitatively different levels. In addition, full-length DCC in collaboration with ROBO3 can antagonize ROBO1 repulsion in vivo. We propose that commissural axons integrate and balance the opposing DCC and Roundabout (ROBO) signaling to ensure proper guidance decisions during midline entry and exit.

Original language	English (US)
Article number	112455
Journal	Cell reports
Volume	42
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2023.112455
State	Published - May 30 2023

Bibliographical note

Funding Information:
This work was supported by the following grants: Masonic Institute for the Developing Brain grant (Z.C.); National Institutes of Health (NIH) R21DA056728 (Z.C.); and NIH R01EY024261 and R01EY033316 (H.J.J.). We thank Yudong Teng at MCDB transgenic facility at the University of Colorado Boulder for generating CRISPR-Cas9-mediated mutant mice, Kelsey R. Arbogast for technical assistance, and Linda McLoon and Yasushi Nakagawa for critical comments on the manuscript. The graphic abstract was created with BioRender.com .

Funding Information:
This work was supported by the following grants: Masonic Institute for the Developing Brain grant (Z.C.); National Institutes of Health (NIH) R21DA056728 (Z.C.); and NIH R01EY024261 and R01EY033316 (H.J.J.). We thank Yudong Teng at MCDB transgenic facility at the University of Colorado Boulder for generating CRISPR-Cas9-mediated mutant mice, Kelsey R. Arbogast for technical assistance, and Linda McLoon and Yasushi Nakagawa for critical comments on the manuscript. The graphic abstract was created with BioRender.com. Z.C. conceived and designed the study. B.D.K. A.L.M. H.N.J. and Z.C. conducted the experiments and analyzed the data. B.D.K. A.L.M. H.N.J. H.J.J. and Z.C. wrote the manuscript. The authors declare no competing interests.

Publisher Copyright:
© 2023 The Authors

Keywords

CP: Developmental biology
CP: Neuroscience
Netrin1/DCC
SLIT/ROBO
alternative splicing
axon guidance
midline switch
silencing model

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "A tug of war between DCC and ROBO1 signaling during commissural axon guidance",

abstract = "Dynamic and coordinated axonal responses to changing environments are critical for establishing neural connections. As commissural axons migrate across the CNS midline, they are suggested to switch from being attracted to being repelled in order to approach and to subsequently leave the midline. A molecular mechanism that is hypothesized to underlie this switch in axonal responses is the silencing of Netrin1/Deleted in Colorectal Carcinoma (DCC)-mediated attraction by the repulsive SLIT/ROBO1 signaling. Using in vivo approaches including CRISPR-Cas9-engineered mouse models of distinct Dcc splice isoforms, we show here that commissural axons maintain responsiveness to both Netrin and SLIT during midline crossing, although likely at quantitatively different levels. In addition, full-length DCC in collaboration with ROBO3 can antagonize ROBO1 repulsion in vivo. We propose that commissural axons integrate and balance the opposing DCC and Roundabout (ROBO) signaling to ensure proper guidance decisions during midline entry and exit.",

keywords = "CP: Developmental biology, CP: Neuroscience, Netrin1/DCC, SLIT/ROBO, alternative splicing, axon guidance, midline switch, silencing model",

author = "Brianna Dailey-Krempel and Martin, {Andrew L.} and Jo, {Ha Neul} and Junge, {Harald J.} and Zhe Chen",

note = "Funding Information: This work was supported by the following grants: Masonic Institute for the Developing Brain grant (Z.C.); National Institutes of Health (NIH) R21DA056728 (Z.C.); and NIH R01EY024261 and R01EY033316 (H.J.J.). We thank Yudong Teng at MCDB transgenic facility at the University of Colorado Boulder for generating CRISPR-Cas9-mediated mutant mice, Kelsey R. Arbogast for technical assistance, and Linda McLoon and Yasushi Nakagawa for critical comments on the manuscript. The graphic abstract was created with BioRender.com . Funding Information: This work was supported by the following grants: Masonic Institute for the Developing Brain grant (Z.C.); National Institutes of Health (NIH) R21DA056728 (Z.C.); and NIH R01EY024261 and R01EY033316 (H.J.J.). We thank Yudong Teng at MCDB transgenic facility at the University of Colorado Boulder for generating CRISPR-Cas9-mediated mutant mice, Kelsey R. Arbogast for technical assistance, and Linda McLoon and Yasushi Nakagawa for critical comments on the manuscript. The graphic abstract was created with BioRender.com. Z.C. conceived and designed the study. B.D.K. A.L.M. H.N.J. and Z.C. conducted the experiments and analyzed the data. B.D.K. A.L.M. H.N.J. H.J.J. and Z.C. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023 The Authors",

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AU - Martin, Andrew L.

AU - Jo, Ha Neul

AU - Junge, Harald J.

AU - Chen, Zhe

N1 - Funding Information: This work was supported by the following grants: Masonic Institute for the Developing Brain grant (Z.C.); National Institutes of Health (NIH) R21DA056728 (Z.C.); and NIH R01EY024261 and R01EY033316 (H.J.J.). We thank Yudong Teng at MCDB transgenic facility at the University of Colorado Boulder for generating CRISPR-Cas9-mediated mutant mice, Kelsey R. Arbogast for technical assistance, and Linda McLoon and Yasushi Nakagawa for critical comments on the manuscript. The graphic abstract was created with BioRender.com . Funding Information: This work was supported by the following grants: Masonic Institute for the Developing Brain grant (Z.C.); National Institutes of Health (NIH) R21DA056728 (Z.C.); and NIH R01EY024261 and R01EY033316 (H.J.J.). We thank Yudong Teng at MCDB transgenic facility at the University of Colorado Boulder for generating CRISPR-Cas9-mediated mutant mice, Kelsey R. Arbogast for technical assistance, and Linda McLoon and Yasushi Nakagawa for critical comments on the manuscript. The graphic abstract was created with BioRender.com. Z.C. conceived and designed the study. B.D.K. A.L.M. H.N.J. and Z.C. conducted the experiments and analyzed the data. B.D.K. A.L.M. H.N.J. H.J.J. and Z.C. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: © 2023 The Authors

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N2 - Dynamic and coordinated axonal responses to changing environments are critical for establishing neural connections. As commissural axons migrate across the CNS midline, they are suggested to switch from being attracted to being repelled in order to approach and to subsequently leave the midline. A molecular mechanism that is hypothesized to underlie this switch in axonal responses is the silencing of Netrin1/Deleted in Colorectal Carcinoma (DCC)-mediated attraction by the repulsive SLIT/ROBO1 signaling. Using in vivo approaches including CRISPR-Cas9-engineered mouse models of distinct Dcc splice isoforms, we show here that commissural axons maintain responsiveness to both Netrin and SLIT during midline crossing, although likely at quantitatively different levels. In addition, full-length DCC in collaboration with ROBO3 can antagonize ROBO1 repulsion in vivo. We propose that commissural axons integrate and balance the opposing DCC and Roundabout (ROBO) signaling to ensure proper guidance decisions during midline entry and exit.

AB - Dynamic and coordinated axonal responses to changing environments are critical for establishing neural connections. As commissural axons migrate across the CNS midline, they are suggested to switch from being attracted to being repelled in order to approach and to subsequently leave the midline. A molecular mechanism that is hypothesized to underlie this switch in axonal responses is the silencing of Netrin1/Deleted in Colorectal Carcinoma (DCC)-mediated attraction by the repulsive SLIT/ROBO1 signaling. Using in vivo approaches including CRISPR-Cas9-engineered mouse models of distinct Dcc splice isoforms, we show here that commissural axons maintain responsiveness to both Netrin and SLIT during midline crossing, although likely at quantitatively different levels. In addition, full-length DCC in collaboration with ROBO3 can antagonize ROBO1 repulsion in vivo. We propose that commissural axons integrate and balance the opposing DCC and Roundabout (ROBO) signaling to ensure proper guidance decisions during midline entry and exit.

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KW - CP: Neuroscience

KW - Netrin1/DCC

KW - SLIT/ROBO

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KW - axon guidance

KW - midline switch

KW - silencing model

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JO - Cell reports

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ER -

A tug of war between DCC and ROBO1 signaling during commissural axon guidance

Abstract

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Keywords

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A tug of war between DCC and ROBO1 signaling during commissural axon guidance

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

Publisher link

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University Imaging Centers

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