Regulation of retinal axon growth by secreted Vax1 homeodomain protein

Retinal ganglion cell (RGC) axons of binocular animals cross the midline at the optic chiasm (OC) to grow toward their synaptic targets in the contralateral brain. Ventral anterior homeobox 1 (Vax1) plays an essential role in the development of the OC by regulating RGC axon growth in a non-cell autonomous manner. In this study, we identify an unexpected function of Vax1 that is secreted from ventral hypothalamic cells and diffuses to RGC axons, where it promotes axonal growth independent of its transcription factor activity. We demonstrate that Vax1 binds to extracellular sugar groups of the heparan sulfate proteoglycans (HSPGs) located in RGC axons. Both Vax1 binding to HSPGs and subsequent penetration into the axoplasm, where Vax1 activates local protein synthesis, are required for RGC axonal growth. Together, our findings demonstrate that Vax1 possesses a novel RGC axon growth factor activity that is critical for the development of the mammalian binocular visual system.

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Faculty Opinions recommendation of ESCRT-II controls retinal axon growth by regulating DCC receptor levels and local protein synthesis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726392446.793520296 ◽

2016 ◽

Author(s):

Esther Stoeckli

Keyword(s):

Protein Synthesis ◽

Axon Growth ◽

Local Protein Synthesis ◽

Retinal Axon ◽

Local Protein

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Differential requirement of F-actin and microtubule cytoskeleton in cue-induced local protein synthesis in axonal growth cones

Neural Development ◽

10.1186/s13064-015-0031-0 ◽

2015 ◽

Vol 10 (1) ◽

pp. 3 ◽

Cited By ~ 19

Author(s):

Michael Piper ◽

Aih Lee ◽

Francisca van Horck ◽

Heather McNeilly ◽

Trina Lu ◽

...

Keyword(s):

Protein Synthesis ◽

Axonal Growth ◽

Growth Cones ◽

Microtubule Cytoskeleton ◽

Local Protein Synthesis ◽

Local Protein

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Erratum to: Differential requirement of F-actin and microtubule cytoskeleton in cue-induced local protein synthesis in axonal growth cones

Neural Development ◽

10.1186/s13064-015-0043-9 ◽

2015 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Michael Piper ◽

Aih Cheun Lee ◽

Francisca P.G van Horck ◽

Heather McNeilly ◽

Trina Bo Lu ◽

...

Keyword(s):

Protein Synthesis ◽

Axonal Growth ◽

Growth Cones ◽

Microtubule Cytoskeleton ◽

Local Protein Synthesis ◽

Local Protein

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Intra-axonal Synthesis of Eukaryotic Translation Initiation Factors Regulates Local Protein Synthesis and Axon Growth in Rat Sympathetic Neurons

Journal of Neuroscience ◽

10.1523/jneurosci.2040-12.2013 ◽

2013 ◽

Vol 33 (17) ◽

pp. 7165-7174 ◽

Cited By ~ 40

Author(s):

A. N. Kar ◽

M. A. MacGibeny ◽

N. M. Gervasi ◽

A. E. Gioio ◽

B. B. Kaplan

Keyword(s):

Translation Initiation ◽

Sympathetic Neurons ◽

Axon Growth ◽

Local Protein Synthesis ◽

Eukaryotic Translation ◽

Initiation Factors ◽

Translation Initiation Factors ◽

Eukaryotic Translation Initiation ◽

Eukaryotic Translation Initiation Factors ◽

Local Protein

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Embryonic neurons of the developing optic chiasm express L1 and CD44, cell surface molecules with opposing effects on retinal axon growth

Neuron ◽

10.1016/0896-6273(94)90307-7 ◽

1994 ◽

Vol 12 (5) ◽

pp. 957-975 ◽

Cited By ~ 101

Author(s):

D.W. Sretavan ◽

L. Feng ◽

E. Puré ◽

L.F. Reichardt

Keyword(s):

Cell Surface ◽

Axon Growth ◽

Optic Chiasm ◽

Cell Surface Molecules ◽

Surface Molecules ◽

Opposing Effects ◽

Retinal Axon ◽

Embryonic Neurons

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Slit2 is essential for correct retinal ganglion cell axon fasciculation and midline crossing in the zebrafish

10.1101/2020.09.25.314062 ◽

2020 ◽

Author(s):

Camila Davison ◽

Flavio R. Zolessi

Keyword(s):

Optic Nerve ◽

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Ganglion Cells ◽

Axon Growth ◽

Amacrine Cells ◽

Optic Chiasm ◽

Retinal Ganglion ◽

Functional Connection ◽

Optic Nerves

ABSTRACTThe functional connection of the retina with the brain implies the extension of retinal ganglion cells axons through a long and tortuous path. Slit-Robo signaling has been implicated in axon growth and guidance in several steps of this journey. Here, we analyzed in detail the expression pattern of slit2 in zebrafish embryos by whole-mount fluorescent in situ hybridization, to extend previous work on this and other species. Major sites of expression are amacrine cells in the retina from 40 hpf, as well as earlier expression around the future optic nerve, anterior to the optic chiasm, two prominent cell groups in the anterior forebrain and the ventral midline of the caudal brain and spinal cord. To further characterize slit2 function in retinal axon growth and guidance, we generated and phenotypically characterized a null mutant for this gene, using CRISPR-Cas9 technology. Although no evident defects were found on intraretinal axon growth or in the formation of the optic tracts or tectal innervation, we observed very characteristic and robust impairment on axon fasciculation at the optic nerves and chiasm. The optic nerves appeared thicker and defasciculated only in maternal-zygotic mutants, while a very particular unilateral nerve-splitting phenotype was evident at the optic chiasm in a good proportion of both zygotic and maternal-zygotic mutants. Our results support the idea of a channeling role for Slit molecules in retinal ganglion cell axons at the optic nerve level, in addition to a function in the segregation of axons coming from each nerve at the optic chiasm.

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GAP-43 mediates retinal axon interaction with lateral diencephalon cells during optic tract formation

Development ◽

10.1242/dev.127.5.969 ◽

2000 ◽

Vol 127 (5) ◽

pp. 969-980

Author(s):

F. Zhang ◽

C. Lu ◽

C. Severin ◽

D.W. Sretavan

Keyword(s):

Growth Cone ◽

Optic Tract ◽

Optic Chiasm ◽

Retinal Ganglion ◽

Wild Type ◽

Targeted Disruption ◽

Entry Zone ◽

Calmodulin Signaling ◽

Retinal Axon ◽

Cell Conditioned Medium

GAP-43 is an abundant intracellular growth cone protein that can serve as a PKC substrate and regulate calmodulin availability. In mice with targeted disruption of the GAP-43 gene, retinal ganglion cell (RGC) axons fail to progress normally from the optic chiasm into the optic tracts. The underlying cause is unknown but, in principle, can result from either the disruption of guidance mechanisms that mediate axon exit from the midline chiasm region or defects in growth cone signaling required for entry into the lateral diencephalic wall to form the optic tracts. Results here show that, compared to wild-type RGC axons, GAP-43-deficient axons exhibit reduced growth in the presence of lateral diencephalon cell membranes. Reduced growth is not observed when GAP-43-deficient axons are cultured with optic chiasm, cortical, or dorsal midbrain cells. Lateral diencephalon cell conditioned medium inhibits growth of both wild-type and GAP-43-deficient axons to a similar extent and does not affect GAP-43-deficient axons more so. Removal or transplant replacement of the lateral diencephalon optic tract entry zone in GAP-43-deficient embryo preparations results in robust RGC axon exit from the chiasm. Together these data show that RGC axon exit from the midline region does not require GAP-43 function. Instead, GAP-43 appears to mediate RGC axon interaction with guidance cues in the lateral diencephalic wall, suggesting possible involvement of PKC and calmodulin signaling during optic tract formation.

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Retinal axon divergence in the optic chiasm: midline cells are unaffected by the albino mutation

Development ◽

10.1242/dev.122.3.859 ◽

1996 ◽

Vol 122 (3) ◽

pp. 859-868 ◽

Cited By ~ 1

Author(s):

R.C. Marcus ◽

L.C. Wang ◽

C.A. Mason

Keyword(s):

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Retinal Pigment ◽

Optic Chiasm ◽

Growth Patterns ◽

Retinal Ganglion ◽

Retinal Explants ◽

Albino Mice ◽

Retinal Axon

The visual pathway in albino animals is abnormal in that there is a smaller number of ipsilaterally projecting retinal ganglion cells. There are two possible sites of gene action that could result in such a defect. The first site is the retina where the amount of pigmentation in the retinal pigment epithelium is correlated with the degree of ipsilateral innervation (La Vail et al. (1978) J. Comp. Neurol. 182, 399–422). The second site is the optic chiasm, the site of retinal axon divergence. We investigated these two possibilities through a combination of in vivo and in vitro techniques. Our results demonstrate that the growth patterns of retinal axons and the cellular composition of the optic chiasm in albino mice are similar to those of normally pigmented mice, consistent with the albino mutation exerting its effects in the retina, and not on the cells from the chiasmatic midline. We directly tested whether the albino mutation affects the chiasm by studying ‘chimeric’ cultures of retinal explants and chiasm cells isolated from pigmented and albino mice. Crossed and uncrossed axons from pigmented or albino retinal explants display the same amount of differential growth when grown on either pigmented or albino chiasm cells, demonstrating that the albino mutation does not disrupt the signals for retinal axon divergence associated with the albino optic chiasm. Furthermore, in vitro, a greater proportion of albino retinal ganglion cells from ventrotemporal retina, origin of uncrossed axons, behave like crossed cells, suggesting that the albino mutation acts by respecifying the numbers of retinal ganglion cells that cross the chiasmatic midline.

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