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

Development ◽  
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.

The metalloproteinase ADAM10 is required for retinal ganglion cell axon guidance in the developing visual systems

2007 ◽  
Vol 30 (4) ◽  
pp. 77
Author(s):  
Y. Y. Chen ◽  
C. L. Hehr ◽  
K. Atkinson-Leadbeater ◽  
J. C. Hocking ◽  
S. McFarlane
Keyword(s):  
Ganglion Cell ◽  
Axon Guidance ◽  
Retinal Ganglion Cell ◽  
Growth Cone ◽  
Expression Patterns ◽  
Optic Tract ◽  
Axon Growth ◽  
Proteolytic Processing ◽  
Retinal Ganglion

Background: The growth cone interprets cues in its environment in order to reach its target. We want to identify molecules that regulate growth cone behaviour in the developing embryo. We investigated the role of A disintegrin and metalloproteinase 10 (ADAM10) in axon guidance in the developing visual system of African frog, Xenopus laevis. Methods: We first examined the expression patterns of adam10 mRNA by in situ hybridization. We then exposed the developing optic tract to an ADAM10 inhibitor, GI254023X, in vivo. Lastly, we inhibited ADAM10 function in diencephalic neuroepithelial cells (through which retinal ganglion cell (RGC) axons extend) or RGCs by electroporating or transfecting an ADAM10 dominant negative (dn-adam10). Results: We show that adam10 mRNA is expressed in the dorsal neuroepithelium over the time RGC axons extend towards their target, the optic tectum. Second, pharmacological inhibition of ADAM10 in an in vivo exposed brain preparation causes the failure of RGC axons to recognize their target at low concentrations (0.5, 1 μM), and the failure of the axons to make a caudal turn in the mid-diencephalon at higher concentration (5 μM). Thus, ADAM10 function is required for RGC axon guidance at two key guidance decisions. Finally, molecular inhibition of ADAM10 function by electroporating dn-adam10 in the brain neuroepithelium causes defects in RGC axon target recognition (57%) and/or defects in caudal turn (12%), as seen with the pharmacological inhibitor. In contrast, molecular inhibition of ADAM10 within the RGC axons has no effect. Conclusions: These data argue strongly that ADAM10 acts cell non-autonomously within the neuroepithelium to regulate the guidance of RGC axons. This study shows for the first time that a metalloproteinase acts in a cell non-autonomous fashion to direct vertebrate axon growth. It will provide important insights into candidate molecules that could be used to reform nerve connections if destroyed because of injury or disease. References Hattori M, Osterfield M, Flanagan JG. Regulated cleavage of a contact-mediated axon repellent. Science 2000; 289(5483):1360-5. Janes PW, Saha N, Barton WA, Kolev MV, Wimmer-Kleikamp SH, Nievergall E, Blobel CP, Himanen JP, Lackmann M, Nikolov DB. Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans. Cell 2005; 123(2):291-304. Pan D, Rubin GM. Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell 1997; 90(2):271-80.

Retinal Ganglion Cell Axon Wiring Establishing the Binocular Circuit

2020 ◽  
Vol 6 (1) ◽  
pp. 215-236
Author(s):  
Carol Mason ◽  
Nefeli Slavi
Keyword(s):  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Molecular Mechanisms ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Optic Tract ◽  
Optic Chiasm ◽  
Retinal Ganglion ◽  
Temporal Features ◽  
Ipsilateral Projection

Binocular vision depends on retinal ganglion cell (RGC) axon projection either to the same side or to the opposite side of the brain. In this article, we review the molecular mechanisms for decussation of RGC axons, with a focus on axon guidance signaling at the optic chiasm and ipsi- and contralateral axon organization in the optic tract prior to and during targeting. The spatial and temporal features of RGC neurogenesis that give rise to ipsilateral and contralateral identity are described. The albino visual system is highlighted as an apt comparative model for understanding RGC decussation, as albinos have a reduced ipsilateral projection and altered RGC neurogenesis associated with perturbed melanogenesis in the retinal pigment epithelium. Understanding the steps for RGC specification into ipsi- and contralateral subtypes will facilitate differentiation of stem cells into RGCs with proper navigational abilities for effective axon regeneration and correct targeting of higher-order visual centers.

Axon routing at the optic chiasm after enzymatic removal of chondroitin sulfate in mouse embryos

Development ◽  
2000 ◽  
Vol 127 (12) ◽  
pp. 2673-2683
Author(s):  
K.Y. Chung ◽  
J.S. Taylor ◽  
D.K. Shum ◽  
S.O. Chan
Keyword(s):  
Chondroitin Sulfate ◽  
Optic Tract ◽  
Optic Chiasm ◽  
Enzymatic Digestion ◽  
Mouse Embryos ◽  
Enzyme Treatment ◽  
Retinal Ganglion ◽  
Retinal Axons ◽  
Before And After ◽  
Brain Slice Preparation

The effects of removing chondroitin sulfate from chondroitin sulfate proteoglycan molecules on guidance of retinal ganglion cell axons at the optic chiasm were investigated in a brain slice preparation of mouse embryos of embryonic day 13 to 15. Slices were grown for 5 hours and growth of dye-labeled axons was traced through the chiasm. After continuous enzymatic digestion of the chondroitin sulfate proteoglycans with chondroitinase ABC, which removes the glycosaminoglycan chains, navigation of retinal axons was disrupted. At embryonic day 13, before the uncrossed projection forms in normal development, many axons deviated from their normal course, crossing the midline at aberrant positions and invading the ventral diencephalon. In slices from embryonic day 14 embryos, axons that would normally form the uncrossed projection at this stage failed to turn into the ipsilateral optic tract. In embryonic day 15 slices, enzyme treatment caused a reduction of the uncrossed projection that develops at this stage. Growth cones in enzyme-treated slices showed a significant increase in the size both before and after they crossed the midline. This indicates that responses of retinal axons to guidance signals at the chiasm have changed after removal of the chondroitin sulfate epitope. We concluded that the chondroitin sulfate moieties of the proteoglycans are involved in patterning the early phase of axonal growth across the midline and at a later stage controlling the axon divergence at the chiasm.

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

Development ◽  
1996 ◽  
Vol 122 (3) ◽  
pp. 859-868 ◽  
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.

scholarly journals Regulation of retinal axon growth by secreted Vax1 homeodomain protein

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Namsuk Kim ◽  
Kwang Wook Min ◽  
Kyung Hwa Kang ◽  
Eun Jung Lee ◽  
Hyoung-Tai Kim ◽  
...  
Keyword(s):  
Axon Growth ◽  
Axonal Growth ◽  
Optic Chiasm ◽  
Homeodomain Protein ◽  
Retinal Ganglion ◽  
Factor Activity ◽  
Local Protein Synthesis ◽  
Hypothalamic Cells ◽  
Retinal Axon ◽  
Local 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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