Control of glial precursor cell development in the mouse optic nerve by sonic hedgehog from retinal ganglion cells.
The development of glial precursor cells in the mammalian optic nerve depends on retinal ganglion cell (RGC) axons, but the signals that mediate this neuron-to-glia interaction have not been fully characterized. Sonic hedgehog (Shh) is expressed by RGCs, and we showed previously that it is required for the specification of astrocyte lineage cells at the optic disc. To study the role of RGC-derived Shh on astrocyte development at later developmental stages, we generated mice with a conditional ablation of Shh in the peripheral retina and analyzed gene expression and glial cell development in the optic nerve. Astrocyte development was initiated in the optic nerves of these mutant mice; however, the expression of Hedgehog (Hh) target genes, Gli1 and Ptch1 and cell cycle genes, Ccnd1 and Cdc25b in the optic nerves were downregulated. Astrocyte proliferation was markedly reduced. Oligodendrocyte precursor cells were fewer in the optic nerves of mutant mice, possibly as a consequence of reduced secretion of growth factors by astrocytes. At a later developmental stage, optic nerve axons displayed signs of Wallerian degeneration, including reduction of astrocyte processes, degenerating glial cells and formation of distended axons. We also demonstrate that the Hh pathway can be activated in optic nerve-derived astrocytes in vitro, but fails to induce cell cycle gene expression and proliferation. RGC-derived Shh signalling isthus necessary in vivo for maintenance of astrocyte proliferation, affecting both axo-glial and normal glial cell development in the optic nerve.
Dakubo
Gabriel D
GD
Ottawa Health Research Institute, Ottawa, ON, Canada K1H 8L6.
Beug
Shawn T
ST
Mazerolle
Chantal J
CJ
Thurig
Sherry
S
Wang
Yaping
Y
Wallace
Valerie A
VA
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D009900:Optic Nerve / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000071676:Zinc Finger Protein GLI1; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism
D056741:Cyclin D; D016213:Cyclins; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; D000071676:Zinc Finger Protein GLI1; C517006:Cdc25b protein, mouse; D020687:cdc25 Phosphatases