Altered astrocyte morphology and vascular development in dystrophin‐<scp>D</scp>p71‐null mice

Giocanti-Aurégan, Audrey; Vacca, Ophélie; Bénard, Romain; Cao, Siyang; Siqueiros, Lourdes Montserrat; Montañéz, Cecilia; Pâques, Michel; Sahel, José‐Alain; Sennlaub, Florian; Guillonneau, Xavier; Rendón, Álvaro; Tadayoni, Ramin

doi:10.1002/glia.22956

Cited by 20 publications

(20 citation statements)

References 60 publications

(82 reference statements)

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“…We believe this to be a lasting result of the delay in angiogenesis, yet it could be due to a remodeling of the network after reaching the retinal margin. Other groups have argued that if vascular branch points are decreased then overall vessel length should increase conversely (Giocanti-Auregan et al, 2016), yet we observe a significant decrease in both. This indicates a general underdevelopment of the vascular network.…”

Section: Discussioncontrasting

confidence: 51%

Sox2 regulates astrocytic and vascular development in the retina

Kautzman

Keeley

Nahmou

et al. 2017

Glia

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Sox2 is a transcriptional regulator that is highly expressed in retinal astrocytes, yet its function in these cells has not previously been examined. To understand its role, we conditionally deleted Sox2 from the population of astrocytes and examined the consequences on retinal development. We found that Sox2 deletion does not alter the migration of astrocytes, but it impairs their maturation, evidenced by the delayed upregulation of glial fibrillary acidic protein (GFAP) across the retina. The centro-peripheral gradient of angiogenesis is also delayed in Sox2-CKO retinas. In the mature retina, we observed lasting abnormalities in the astrocytic population evidenced by the sporadic loss of GFAP immunoreactivity in the peripheral retina as well as by the aberrant extension of processes into the inner retina. Blood vessels in the adult retina are also under-developed and show a decrease in the frequency of branch points and in total vessel length. The developmental relationship between maturing astrocytes and angiogenesis suggests a causal relationship between the astrocytic loss of Sox2 and the vascular architecture in maturity. We suggest that the delay in astrocytic maturation and vascular invasion may render the retina hypoxic, thereby causing the abnormalities we observe in adulthood. These studies uncover a novel role for Sox2 in the development of retinal astrocytes and indicate that its removal can lead to lasting changes to retinal homeostasis.

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Section: Discussioncontrasting

confidence: 51%

Sox2 regulates astrocytic and vascular development in the retina

Kautzman

Keeley

Nahmou

et al. 2017

Glia

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“…This possibility is supported by the following experimental finding. That is, in mice lacking dystrophin 71, the major protein product of the dystrophin gene, GFAP‐immunopositive astrocytes and their processes reduced significantly comparing to the wild type mice (Giocanti‐Auregan et al, ). This can be explained by the failure of anchor proteins to pull GFAP fibers toward the membrane at the processes when volemic expansion occurs.…”

Section: Mechanisms Underlying Gfap Guiding Rolementioning

confidence: 99%

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

Liu

et al. 2019

Glia

103

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Glial fibrillary acidic protein (GFAP), a type III intermediate filament, is a marker of mature astrocytes. The expression of GFAP gene is regulated by many transcription factors (TFs), mainly Janus kinase‐2/signal transducer and activator of transcription 3 cascade and nuclear factor κ‐light‐chain‐enhancer of activated B cell signaling. GFAP expression is also modulated by protein kinase and other signaling molecules that are elicited by neuronal activity and hormones. Abnormal expression of GFAP proteins occurs in neuroinflammation, neurodegeneration, brain edema‐eliciting diseases, traumatic brain injury, psychiatric disorders and others. GFAP, mainly in α‐isoform, is the major component of cytoskeleton and the scaffold of astrocytes, which is essential for the maintenance of astrocytic structure and shape. GFAP also has highly morphological plasticity because of its quick changes in assembling and polymerizing states in response to environmental challenges. This plasticity and its corresponding cellular morphological changes endow astrocytes the functions of physical barrier between adjacent neurons and stabilizer of extracellular environment. Moreover, GFAP colocalizes and even molecularly associates with many functional molecules. This feature allows GFAP to function as a platform for direct interactions between different molecules. Last, GFAP involves transportation and localization of other functional proteins and thus serves as a protein transport guide in astrocytes. This guiding role of GFAP involves an elastic retraction and extension cytoskeletal network that couples with GFAP reassembling, transporting, and membrane protein recycling machinery. This paper reviews our current understanding of the expression and functions of GFAP as well as their regulation.

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“…It will be important to examine the role of additional growth factors in this system. As for contactmediated guidance cues, many ECM components and interactors such as laminins (Gnanaguru et al, 2013), integrins (Hirota et al, 2011;Samarelli et al, 2014), dystrophin (Giocanti-Auregan et al, 2016), and proteoglycans (Stenzel et al, 2011) are very likely involved. However, their widespread expression makes these unlikely candidates to mediate a specific astrocyte-endothelial interaction.…”

Section: Patterning Of Retinal Blood Vesselsmentioning

confidence: 99%

Astrocytes follow ganglion cell axons to establish an angiogenic template during retinal development

O’Sullivan

Puñal

Kerstein

et al. 2017

Glia

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Immature astrocytes and blood vessels enter the developing mammalian retina at the optic nerve head, and migrate peripherally to colonize the entire retinal nerve fiber layer (RNFL). Retinal vascularization is arrested in retinopathy of prematurity (ROP), a major cause of bilateral blindness in children. Despite their importance in normal development and ROP, the factors that control vascularization of the retina remain poorly understood. Because astrocytes form a reticular network that appears to provide a substrate for migrating endothelial cells, they have long been proposed to guide angiogenesis. However, whether astrocytes do in fact impose a spatial pattern on developing vessels remains unclear, and how astrocytes themselves are guided is unknown. Here we explore the cellular mechanisms that ensure complete retinal coverage by astrocytes and blood vessels in mouse. We find that migrating astrocytes associate closely with the axons of retinal ganglion cells (RGCs), their neighbors in the RNFL. Analysis of Robo1; Robo2 mutants, in which RGC axon guidance is disrupted, and Math5 (Atoh7) mutants, which lack RGCs, reveals that RGCs provide directional information to migrating astrocytes that sets them on a centrifugal trajectory. Without this guidance, astrocytes exhibit polarization defects, fail to colonize the peripheral retina, and display abnormal fine-scale spatial patterning. Further, using cell type-specific chemical-genetic tools to selectively ablate astrocytes, we show that the astrocyte template is required for angiogenesis and vessel patterning. Our results are consistent with a model whereby RGC axons guide formation of an astrocytic network that subsequently directs vessel development.

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Altered astrocyte morphology and vascular development in dystrophin‐Dp71‐null mice

Cited by 20 publications

References 60 publications

Sox2 regulates astrocytic and vascular development in the retina

Sox2 regulates astrocytic and vascular development in the retina

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

Astrocytes follow ganglion cell axons to establish an angiogenic template during retinal development

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