Transgenic Expression of Constitutively Active RAC1 Disrupts Mouse Rod Morphogenesis

Song, Hailong; Bush, Ronald A.; Vijayasarathy, Camasamudram; Fariss, Robert N.; Kjellström, Sten; Sieving, Paul A.

doi:10.1167/iovs.13-13649

Cited by 20 publications

(33 citation statements)

References 57 publications

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“…As many of these signaling molecules are potential targets or downstream effectors of GRF signaling, their study might provide clues to ascertain the exact molecular mechanisms responsible for the GRF2-dependent defects of cone nuclear movement described in this report. Nevertheless, we should also mention that, in contrast to most models of defective cone nuclear movement, where the cellular morphological alterations are usually accompanied by photoreceptor cell death (Pow and Sullivan, 2007;Song et al, 2014;Trifunovićet al, 2010), the cones of GRF2-KO retinas presented normal morphology and their survival was not compromised (at least until our analysis at 5 months of age), suggesting significant mechanistic proximity between GRF2 and control of cone nuclear movements, although further functional studies are needed to confirm this notion. Even if the survival of cone photoreceptors is not compromised in GRF2-depleted retinas, their defective ERG patterns clearly indicate that their functional role in the vision process is compromised, and it will be interesting to determine whether the reduced ERG responses are due to alterations in the synaptogenesis (Rich et al, 1997) of the cone cells in retinas lacking GRF2.…”

Section: Discussionmentioning

confidence: 68%

“…Previous studies of neuroepithelial differentiation and retinal degeneration processes occurring in mouse models (García Arguinzonis et al, 2002;Song et al, 2014;Trifunovićet al, 2010) or in humans (Jacobson et al, 2003;Lotery, 2001;Mehalow et al, 2003;Pow and Sullivan, 2007;van de Pavert et al, 2004van de Pavert et al, , 2007 have provided useful clues regarding the cellular mechanisms and signaling molecules that might be relevant for the origination of the novel GRF2-dependent phenotypes described in this report. Consistent with those reports, our immunolabeling analyses identified structural disruptions of the OLM and alterations of the expression patterns of several signaling molecules that were closely associated to the defective cone nuclear migration phenotype observed in GRF2-depleted retinas.…”

Section: Discussionmentioning

confidence: 68%

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RasGRF2 controls nuclear migration in postnatal retinal cone photoreceptors

Jimeno

Gómez

Calzada

et al. 2016

Journal of Cell Science

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Detailed immunocytochemical analyses comparing wild-type (WT), GRF1-knockout (KO), GRF2-KO and GRF1/2 double-knockout (DKO) mouse retinas uncovered the specific accumulation of misplaced, 'ectopic' cone photoreceptor nuclei in the photoreceptor segment (PS) area of retinas from GRF2-KO and GRF1/2-DKO, but not of WT or GRF1-KO mice. Localization of ectopic nuclei in the PS area of GRF2-depleted retinas occurred postnatally and peaked between postnatal day (P)11 and P15. Mechanistically, the generation of this phenotype involved disruption of the outer limiting membrane and intrusion into the PS layer by cone nuclei displaying significant perinuclear accumulation of signaling molecules known to participate in nuclear migration and cytoskeletal reorganization, such as PAR3, PAR6 and activated, phosphorylated forms of PAK, MLC2 and VASP. Electroretinographic recordings showed specific impairment of cone-mediated retinal function in GRF2-KO and GRF1/2-DKO retinas compared with WT controls. These data identify defective cone nuclear migration as a novel phenotype in mouse retinas lacking GRF2 and support a crucial role of GRF2 in control of the nuclear migration processes required for proper postnatal development and function of retinal cone photoreceptors.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 68%

RasGRF2 controls nuclear migration in postnatal retinal cone photoreceptors

Jimeno

Gómez

Calzada

et al. 2016

Journal of Cell Science

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“…[22][23][24] In particular, constitutively active Rac1 disrupts rod morphogenesis in mice, with defects in polarity and migration. It is therefore possible that the retinal dystrophy and macular hypoplasia that are present in four of our eight patients relate to a loss of Rac1 regulation by HACE1.…”

Section: Discussionmentioning

confidence: 99%

HACE1deficiency causes an autosomal recessive neurodevelopmental syndrome

et al. 2015

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BackgroundThe genetic aetiology of neurodevelopmental defects is extremely diverse, and the lack of distinctive phenotypic features means that genetic criteria are often required for accurate diagnostic classification. We aimed to identify the causative genetic lesions in two families in which eight affected individuals displayed variable learning disability, spasticity and abnormal gait.MethodsAutosomal recessive inheritance was suggested by consanguinity in one family and by sibling recurrences with normal parents in the second. Autozygosity mapping and exome sequencing, respectively, were used to identify the causative gene.ResultsIn both families, biallelic loss-of-function mutations in HACE1 were identified. HACE1 is an E3 ubiquitin ligase that regulates the activity of cellular GTPases, including Rac1 and members of the Rab family. In the consanguineous family, a homozygous mutation p.R219* predicted a truncated protein entirely lacking its catalytic domain. In the other family, compound heterozygosity for nonsense mutation p.R748* and a 20-nt insertion interrupting the catalytic homologous to the E6-AP carboxyl terminus (HECT) domain was present; western blot analysis of patient cells revealed an absence of detectable HACE1 protein.ConclusionHACE1 mutations underlie a new autosomal recessive neurodevelopmental disorder. Previous studies have implicated HACE1 as a tumour suppressor gene; however, since cancer predisposition was not observed either in homozygous or heterozygous mutation carriers, this concept may require re-evaluation.

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“…50 These mice show early-age disruption of rod morphogenesis and also exhibit progressive photoreceptor degeneration with aging. Here, we have focused on the biologic role of NOX in the degeneration stages as separate from our previous description of the developmental defects observed in these transgenic (Tg)–CA-RAC1 mice.…”

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confidence: 99%

NADPH Oxidase Contributes to Photoreceptor Degeneration in Constitutively Active RAC1 Mice

Song

Vijayasarathy

Zeng

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PurposeThe active form of small GTPase RAC1 is required for activation of NADPH oxidase (NOX), which in turn generates reactive oxygen species (ROS) in nonphagocytic cells. We explored whether NOX-induced oxidative stress contributes to rod degeneration in retinas expressing constitutively active (CA) RAC1.MethodsTransgenic (Tg)–CA-RAC1 mice were given apocynin (10 mg/kg, intraperitoneal), a NOX inhibitor, or vehicle daily for up to 13 weeks. Superoxide production and oxidative damage were assessed by dihydroethidium staining and by protein carbonyls and malondialdehyde levels, respectively. Outer nuclear layer (ONL) cells were counted and electroretinogram (ERG) amplitudes measured in Tg-CA-RAC1 mice. Outer nuclear layer cells were counted in wild-type (WT) mice after transfer of CA-Rac1 gene by subretinal injection of AAV8-pOpsin-CA Rac1-GFP.ResultsTransgenic-CA-RAC1 retinas had significantly fewer photoreceptor cells and more apoptotic ONL cells than WT controls from postnatal week (Pw) 3 to Pw13. Superoxide accumulation and protein and lipid oxidation were increased in Tg-CA-RAC1 retinas and were reduced in mice treated with apocynin. Apocynin reduced the loss of photoreceptors and increased the rod ERG a- and b-wave amplitudes when compared with vehicle-injected transgenic controls. Photoreceptor loss was also observed in regions of adult WT retina transduced with AAV8-pOpsin-CA Rac1-GFP but not in neighboring regions that were not transduced or in AAV8-pOpsin-GFP–transduced retinas.ConclusionsConstitutively active RAC1 promotes photoreceptor cell death by oxidative damage that occurs, at least partially, through NOX-induced ROS. Reactive oxygen species are likely involved in multiple forms of retinal degenerations, and our results support investigating RAC1 inhibition as a therapeutic approach that targets this disease pathway.

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Transgenic Expression of Constitutively Active RAC1 Disrupts Mouse Rod Morphogenesis

Cited by 20 publications

References 57 publications

RasGRF2 controls nuclear migration in postnatal retinal cone photoreceptors

RasGRF2 controls nuclear migration in postnatal retinal cone photoreceptors

HACE1deficiency causes an autosomal recessive neurodevelopmental syndrome

NADPH Oxidase Contributes to Photoreceptor Degeneration in Constitutively Active RAC1 Mice

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