The Netrin 1 Receptors<i>Unc5h3</i>and<i>Dcc</i>Are Necessary at Multiple Choice Points for the Guidance of Corticospinal Tract Axons

Finger, Jacqueline H.; Bronson, Rod T.; Harris, Belinda S.; Johnson, Kenneth R.; Przyborski, Stefan; Ackerman, Susan L.

doi:10.1523/jneurosci.22-23-10346.2002

Cited by 177 publications

(188 citation statements)

References 42 publications

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“…Apoptosis in response to external survival cues may require a receptor, such as UNC5H1, and the presence of NRAGE to transmit the death signal. Once a cell has begun to differentiate, studies have shown that some neurons use UNC5Hs to mediate axon guidance or cell migration (3,7,11,34,35). Down-regulation of NRAGE would ensure that a differentiated neuron responding to guidance cues is no longer able to send an apoptotic signal through UNC5H1.…”

Section: Discussionmentioning

confidence: 99%

UNC5H1 Induces Apoptosis via Its Juxtamembrane Region through an Interaction with NRAGE

Williams

Strickland

Watanabe

et al. 2003

Journal of Biological Chemistry

103

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The UNC5Hs are axon guidance receptors that mediate netrin-1-dependent chemorepulsion, and dependence receptors that mediate netrin-1-independent apoptosis. Here, we report an interaction between UNC5H1 and NRAGE. Our experiments show that this interaction is responsible for apoptosis induced by UNC5H1, and this level of apoptosis is greater than the amount induced by either UNC5H2 or UNC5H3. We mapped the NRAGE binding domain of UNC5H1 to its ZU-5 domain and show that this region, in addition to an adjacent PEST sequence, is required for UNC5H1-mediated apoptosis. Chimeric UNC5H2 and UNC5H3 receptors, containing the NRAGE binding domain and PEST sequence of UNC5H1, bind NRAGE and cause increased levels of apoptosis. UNC5H1 expression does not induce apoptosis in differentiated PC12 cells, which down-regulate NRAGE, but induces apoptosis in native PC12 cells that endogenously express high levels of NRAGE and in differentiated PC12 cells when NRAGE is overexpressed. Together, these results demonstrate a mechanism for UNC5H1-mediated apoptosis that requires an interaction with the MAGE protein NRAGE.Apoptosis plays a critical role in determining the size and shape of the vertebrate nervous system (1). The execution phase of the apoptotic program in neurons is well characterized and, as with most cell types, depends on the activation of intracellular proteases, primarily caspases (2). In contrast, it is not well understood how cues from the environment regulate this process during development of the nervous system. UNC-5 was originally characterized in Caenorhabditis elegans as a gene required for axonal repulsion in netrin/UNC-6 responsive neurons (3, 4). The vertebrate members of this family (UNC5H1, 2, and 3) (5, 6), together with C. elegans UNC-5 (4) and Drosophila Unc5 (7), comprise a subgroup of the Ig superfamily of receptors. The UNC5s contain two Ig and two thrombospondin type-I repeats in the extracellular domain. In addition, their cytoplasmic domains contain regions of homology with other proteins: 1) a ZU-5 domain homologous to Zona Occludens-1, a protein implicated in tight-junction formation (8); and 2) a C-terminal death domain, a domain first identified as the pro-apoptotic region of tumor necrosis factor receptor-1 (9, 10). In a netrin-1 gradient, a complex of UNC5H1 and DCC mediates repulsion (11), although there is evidence suggesting that short range repulsion by netrin-1 may be mediated by UNC5 alone (3, 7). NRAGE (Dlxin-1, MAGE-D1) is a recently identified molecule belonging to the MAGE (melanoma antigen) protein family. There are currently over 25 MAGE proteins in humans, characterized by the presence of a MAGE homology domain. The expression of many MAGE proteins is restricted to cancer cells (12); however, recent studies have revealed a role for two MAGE proteins in the nervous system. One MAGE family member, necdin, is thought to maintain the differentiated state of post-mitotic neurons by preventing entry into the cell cycle (13,14). Another MAGE family member, NRAGE, is expressed in the...

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Section: Discussionmentioning

confidence: 99%

UNC5H1 Induces Apoptosis via Its Juxtamembrane Region through an Interaction with NRAGE

Williams

Strickland

Watanabe

et al. 2003

Journal of Biological Chemistry

103

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“…For example, Satb2 mutants show reduced expression of Unc5H3, a well-characterized axonal guidance receptor (9). In Unc5H3 mutants, subcerebral axons fail to descend past the decussation into the spinal cord (13), raising the possibility that Satb2 knockouts display a similar phenotype due to reduced expression of Unc5H3. An alternative possibility is that Satb2 may play a non-cell autonomous role in guiding subcerebral axons to the spinal cord.…”

Section: Visualization Of Callosal and Subcortical Axonal Connectionsmentioning

confidence: 99%

“…In particular, three axonal guidance molecules (EphA4, PlxnA4, and Unc5H3) are down-regulated in upper layers of mice lacking Satb2. Prior studies have implicated Ephs and ephrins in callosal development (13,28,29). EphA4 is normally expressed in upper layer callosal neurons and the glial wedge (28).…”

Section: Expression Of Epha4 and Unc5h3 Restores Callosal Projections Inmentioning

confidence: 99%

“…In Satb2 mutants, EphA4 expression is lost in cortical neurons, but expression in the glial wedge is maintained (9). Unc5H3 mutants have no reported callosal deficiencies (13), but mice lacking Netrin, a ligand for Unc5H3, lack both the CC and the anterior commissure (29,30). To test the hypothesis that one or more of these genes is required for the proper guidance of callosal axons to their destinations, we attempted to rescue the formation of callosal projections in Satb2 mutants by reintroducing the expression of individual axon guidance molecules into upper layer neurons.…”

Section: Expression Of Epha4 and Unc5h3 Restores Callosal Projections Inmentioning

confidence: 99%

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A network of genetic repression and derepression specifies projection fates in the developing neocortex

Srinivasan

Leone

Bateson

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

160

171

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Neurons within each layer in the mammalian cortex have stereotypic projections. Four genes-Fezf2, Ctip2, Tbr1, and Satb2-regulate these projection identities. These genes also interact with each other, and it is unclear how these interactions shape the final projection identity. Here we show, by generating double mutants of Fezf2, Ctip2, and Satb2, that cortical neurons deploy a complex genetic switch that uses mutual repression to produce subcortical or callosal projections. We discovered that Tbr1, EphA4, and Unc5H3 are critical downstream targets of Satb2 in callosal fate specification. This represents a unique role for Tbr1, implicated previously in specifying corticothalamic projections. We further show that Tbr1 expression is dually regulated by Satb2 and Ctip2 in layers 2-5. Finally, we show that Satb2 and Fezf2 regulate two disease-related genes, Auts2 (Autistic Susceptibility Gene2) and Bhlhb5 (mutated in Hereditary Spastic Paraplegia), providing a molecular handle to investigate circuit disorders in neurodevelopmental diseases.cell fate | cerebral cortex | axon guidance | transcription factor

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“…Mutations in genes such as netrin1 (21), DCC and Unc5h3 (22), and slit1͞2 (23) cause defects in corpus callosum and pyramidal tract development; thus, we examined the expression of a variety of axon guidance molecules, including netrins and their receptors, Robo and slit family members, and semaphorins and plexins. Of 36 genes tested, no obvious differences in expression were detected at E14, E15, E17, or P0 ( Fig.…”

Section: Fezl Regulates the Expression Of Several Genes Expressed In mentioning

confidence: 99%

Fezl regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex

Chen

Schaevitz

McConnell

2005

Proc. Natl. Acad. Sci. U.S.A.

335

400

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During the development of the cerebral cortex, progenitor cells produce neurons that migrate to laminar positions appropriate for their birth dates, adopt specific neuronal identities, and form appropriate local and long-distance axonal connections. Here, we report that forebrain embryonic zinc-finger-like protein (Fezl), a putative zinc-finger transcriptional repressor, is required for the differentiation of projection neurons in cortical layer 5. In Fezldeficient mice, these neurons display molecular, morphological, and axonal targeting defects. The corticospinal tract was absent in Fezl ؊/؊ mice, corticotectal and pontine projections were severely reduced, and Fezl-expressing neurons formed aberrant axonal projections. The expression of many molecular markers for deeplayer neurons was reduced or absent in the Fezl ؊/؊ cerebral cortex. Most strikingly, Ctip2, a transcription factor required for the formation of the corticospinal tract, was not expressed in the Fezl-deficient cortex. These results suggest that Fezl regulates the differentiation of layer 5 subcortical projection neurons.axon guidance ͉ cell fate ͉ corticospinal tract ͉ zinc-finger transcription factor

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The Netrin 1 ReceptorsUnc5h3andDccAre Necessary at Multiple Choice Points for the Guidance of Corticospinal Tract Axons

Cited by 177 publications

References 42 publications

UNC5H1 Induces Apoptosis via Its Juxtamembrane Region through an Interaction with NRAGE

UNC5H1 Induces Apoptosis via Its Juxtamembrane Region through an Interaction with NRAGE

A network of genetic repression and derepression specifies projection fates in the developing neocortex

Fezl regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex

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