Crossing the embryonic midline: molecular mechanisms regulating axon responsiveness at an intermediate target

Neuhaus-Follini, Alexandra; Bashaw, Greg J.

doi:10.1002/wdev.185

Cited by 31 publications

(21 citation statements)

References 91 publications

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“…IMP2 regulation of other targets might also contribute, since our CLIP list includes mRNAs for additional proteins involved in axon growth and guidance, including some known to have midline guidance phenotypes. Moreover, RNA-based mechanisms of the type studied here (Brittis et al, 2002;Colak et al, 2013;Preitner et al, 2013) are likely to act in concert with switch mechanisms at other molecular levels (Nawabi and Castellani, 2011;Neuhaus-Follini and Bashaw, 2015;Alther et al, 2016) to accomplish this complex biological process.…”

Section: Imp2 Is Required For Normal Commissural Axon Trajectories Inmentioning

confidence: 99%

IMP2 axonal localization, RNA interactome, and function in the development of axon trajectories

Preitner

Quan

et al. 2016

Development

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RNA-based regulatory mechanisms play important roles in the development and plasticity of neural circuits and neurological disease. Developing axons provide a model well suited to the study of RNA-based regulation, and contain specific subsets of mRNAs that are locally translated and have roles in axon pathfinding. However, the RNA-binding proteins involved in axon pathfinding, and their corresponding mRNA targets, are still largely unknown. Here we find that the RNA-binding protein IMP2 (Igf2bp2) is strikingly enriched in developing axon tracts, including in spinal commissural axons. We used the HITS-CLIP approach to perform a genome-wide identification of RNAs that interact directly with IMP2 in the native context of developing mouse brain. This IMP2 interactome was highly enriched for mRNA targets related to axon guidance. Accordingly, IMP2 knockdown in the developing spinal cord led to strong defects in commissural axon trajectories at the midline intermediate target.These results reveal a highly distinctive axonal enrichment of IMP2, show that it interacts with a network of axon guidance-related mRNAs, and reveal that it is required for normal axon pathfinding during vertebrate development.

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Section: Imp2 Is Required For Normal Commissural Axon Trajectories Inmentioning

confidence: 99%

IMP2 axonal localization, RNA interactome, and function in the development of axon trajectories

Preitner

Quan

et al. 2016

Development

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“…One of the best-studied examples of this phenomenon is the growth of commissural axons across the ventral midline of the embryonic central nervous system in bilaterally symmetric animals (reviewed in Neuhaus-Follini and Bashaw, 2015). Throughout the period of time when commissural axons are crossing the midline, cells at the midline produce a host of chemotropic cues, including both attractants and repellents.…”

Section: Introductionmentioning

confidence: 99%

The Intracellular Domain of the Frazzled/DCC Receptor Is a Transcription Factor Required for Commissural Axon Guidance

Neuhaus-Follini

Bashaw

2015

Neuron

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Summary In commissural neurons of Drosophila, the conserved Frazzled (Fra)/Deleted in Colorectal Cancer (DCC) receptor promotes midline axon crossing by signaling locally in response to Netrin and by inducing transcription of commissureless (comm), an antagonist of Slit-Roundabout midline repulsion, through an unknown mechanism. Here, we show that Fra is cleaved to release its intracellular domain (ICD), which shuttles between the cytoplasm and the nucleus, where it functions as a transcriptional activator. Rescue and gain-of-function experiments demonstrate that the Fra ICD is sufficient to regulate comm expression and that both γ-secretase proteolysis of Fra and Fra's function as a transcriptional activator are required for its ability to regulate comm in vivo. Our data uncover an unexpected role for the Fra ICD as a transcription factor whose activity regulates the responsiveness of commissural axons at the midline and raise the possibility that nuclear signaling may be a common output of axon guidance receptors.

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“…For the majority of midline circuits, appropriate circuit formation requires axons to cross the midline. Netrin and its attractive receptor DCC, or Frazzled (Fra) in Drosophila , are highly conserved guidance factors known to promote midline crossing (Harris et al, 1996; Kennedy et al, 1994; Kolodziej et al, 1996; Neuhaus-Follini and Bashaw, 2015a; Serafini et al, 1994). Mutations in DCC are associated with movement disorders in zebrafish, mice and humans (Jain et al, 2014; Rabe Bernhardt et al, 2012; Srour et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Sema-1a Reverse Signaling Promotes Midline Crossing in Response to Secreted Semaphorins

2017

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SUMMARY Commissural axons must cross the midline to form functional midline circuits. In the invertebrate nerve cord and vertebrate spinal cord, midline crossing is mediated in part by Netrin-dependent chemoattraction. Loss of crossing, however, is incomplete in mutants for Netrin or its receptor Frazzled/DCC, suggesting the existence of additional pathways. We identified the transmembrane Semaphorin, Sema-1a, as an important regulator of midline crossing in the Drosophila CNS. We show that in response to the secreted Semaphorins Sema-2a and Sema-2b, Sema-1a functions as a receptor to promote crossing independently of Netrin. In contrast to other examples of reverse signaling where Sema1a triggers repulsion through activation of Rho in response to Plexin binding, in commissural neurons Sema-1a acts independently of Plexins to inhibit Rho to promote attraction to the midline. These findings suggest that Sema-1a reverse signaling can elicit distinct axonal responses depending on differential engagement of distinct ligands and signaling effectors.

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Crossing the embryonic midline: molecular mechanisms regulating axon responsiveness at an intermediate target

Cited by 31 publications

References 91 publications

IMP2 axonal localization, RNA interactome, and function in the development of axon trajectories

IMP2 axonal localization, RNA interactome, and function in the development of axon trajectories

The Intracellular Domain of the Frazzled/DCC Receptor Is a Transcription Factor Required for Commissural Axon Guidance

Sema-1a Reverse Signaling Promotes Midline Crossing in Response to Secreted Semaphorins

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