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

Neuhaus-Follini, Alexandra; Bashaw, Greg J.

doi:10.1016/j.neuron.2015.08.006

Cited by 48 publications

(54 citation statements)

References 90 publications

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“…The ap neurons express low levels of fra (see below), do not express isl (Thor and Thomas, 1997; and data not shown), and do not cross the midline. Fra over-expression causes ectopic midline crossing of ap axons (Neuhaus-Follini and Bashaw, 2015; O ‘Donnell and Bashaw, 2013). We found that over-expression of Isl with ap-Gal4 produces high levels of midline crossing, phenocopying the effect of Fra over-expression (Figure 2F,H).…”

Section: Resultsmentioning

confidence: 99%

Islet Coordinately Regulates Motor Axon Guidance and Dendrite Targeting through the Frazzled/DCC Receptor

Santiago¹,

Bashaw²

2017

Cell Reports

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Summary Motor neuron axon targeting in the periphery is correlated with the positions of motor neuron inputs in the CNS, but how these processes are coordinated to form a myotopic map remains poorly understood. We show that the LIM homeodomain factor Islet (Isl) controls targeting of both axons and dendrites in Drosophila motor neurons through regulation of the Frazzled (Fra)/DCC receptor. Isl is required for fra expression in ventrally-projecting motor neurons, and isl and fra mutants have similar axon guidance defects. Single-cell labeling indicates that isl and fra are also required for dendrite targeting in a subset-specific way. Finally, over-expression of Fra rescues axon and dendrite targeting defects in isl mutants. These results indicate that Fra acts downstream of Islet in both the periphery and the CNS, demonstrating how a single regulatory relationship is used in multiple cellular compartments to coordinate neural circuit wiring.

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Section: Resultsmentioning

confidence: 99%

Islet Coordinately Regulates Motor Axon Guidance and Dendrite Targeting through the Frazzled/DCC Receptor

Santiago¹,

Bashaw²

2017

Cell Reports

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“…We observed this interaction in a number of different backgrounds, first with the Fra dominant negative (FraΔC), as well as with the fra and NetAB mutants, and then most dramatically with the sema-1a, fra or NetAB; sema-1a double mutants. Our lab previously uncovered a Netrin-independent role for Fra as well as a role for Robo2 in promoting midline crossing (Evans et al, 2015; Neuhaus-Follini and Bashaw, 2015b; Yang et al, 2009). Both of these pathways function by negatively regulating Robo1 repulsion at the midline.…”

Section: Discussionmentioning

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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“…Accumulating evidence supports the concept that specific aspects of neuronal morphogenesis may be controlled by dynamic transcriptional feedback programs in response to transmembrane receptor signaling at growth cones or synapses (Bao et al, 2004;Yang et al, 2009;Neuhaus-Follini & Bashaw, 2015). For example, the axon guidance receptor Frazzled (Fra), which is the Drosophila homologue of DCC and expressed in neuronal growth cones, was shown to be cleaved by c-secretase releasing its intracellular domain (Neuhaus-Follini & Bashaw, 2015).…”

Section: Functions Of Dscam-dependent Membrane-to-nucleus Signaling Imentioning

confidence: 99%

“…The Fra ICD translocates to the nucleus where it functions as a transcriptional activator regulating the expression of commissureless in vivo (Yang et al, 2009;Neuhaus-Follini & Bashaw, 2015). Commissureless on the other hand is a factor controlling midline crossing by negatively regulating the amount of repulsive Robo receptors at the cell surface of precrossing commissural axons (Yang et al, 2009;Neuhaus-Follini & Bashaw, 2015). Here we show that nuclear enrichment of the DSCAM ICD leads to transcriptional up-regulation of the repulsive axon guidance receptor Unc5a as well as down-regulation of the neurotrophin receptor Ntrk2 in primary neuron cultures.…”

Section: Functions Of Dscam-dependent Membrane-to-nucleus Signaling Imentioning

confidence: 99%

Nuclear import of the DSCAM ‐cytoplasmic domain drives signaling capable of inhibiting synapse formation

et al. 2019

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DSCAM and DSCAML1 are immunoglobulin and cell adhesion‐type receptors serving important neurodevelopmental functions including control of axon growth, branching, neurite self‐avoidance, and neuronal cell death. The signal transduction mechanisms or effectors of DSCAM receptors, however, remain poorly characterized. We used a human ORFeome library to perform a high‐throughput screen in mammalian cells and identified novel cytoplasmic signaling effector candidates including the Down syndrome kinase Dyrk1a, STAT3, USP21, and SH2D2A. Unexpectedly, we also found that the intracellular domains (ICDs) of DSCAM and DSCAML1 specifically and directly interact with IPO5, a nuclear import protein of the importin beta family, via a conserved nuclear localization signal. The DSCAM ICD is released by γ‐secretase‐dependent cleavage, and both the DSCAM and DSCAML1 ICDs efficiently translocate to the nucleus. Furthermore, RNA sequencing confirms that expression of the DSCAM as well as the DSCAML1 ICDs alone can profoundly alter the expression of genes associated with neuronal differentiation and apoptosis, as well as synapse formation and function. Gain‐of‐function experiments using primary cortical neurons show that increasing the levels of either the DSCAM or the DSCAML1 ICD leads to an impairment of neurite growth. Strikingly, increased expression of either full‐length DSCAM or the DSCAM ICD, but not the DSCAML1 ICD, significantly decreases synapse numbers in primary hippocampal neurons. Taken together, we identified a novel membrane‐to‐nucleus signaling mechanism by which DSCAM receptors can alter the expression of regulators of neuronal differentiation and synapse formation and function. Considering that chromosomal duplications lead to increased DSCAM expression in trisomy 21, our findings may help uncover novel mechanisms contributing to intellectual disability in Down syndrome.

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

Cited by 48 publications

References 90 publications

Islet Coordinately Regulates Motor Axon Guidance and Dendrite Targeting through the Frazzled/DCC Receptor

Islet Coordinately Regulates Motor Axon Guidance and Dendrite Targeting through the Frazzled/DCC Receptor

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

Nuclear import of the DSCAM ‐cytoplasmic domain drives signaling capable of inhibiting synapse formation

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