Smad4 Is Required Predominantly in the Developmental Processes Dependent on the BMP Branch of the TGF-β Signaling System in the Embryonic Mouse Retina

Murali, Deepa; Kawaguchi-Niida, Motoko; Deng, Chu‐Xia; Furuta, Yasuhide

doi:10.1167/iovs.10-5940

Cited by 10 publications

(10 citation statements)

References 57 publications

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“…MO-mediated down-regulation of tgfβr1 induced a phenotype characterized by abnormal body and head structures, including microphthalmia ( Fig 1B and 1C ). This phenotype was in accordance with what was previously shown in other TGF-β pathway component ablation in various model systems, reinforcing the importance of this signaling pathway for ocular development, starting from early eye morphogenesis, retinal pigment epithelium fate determination, retina programmed cell death (PCD) and neurogenesis [ 2 , 4 , 19 , 20 ]. Indeed, TUNEL assay revealed a strong increase of cell death in the eyes of MO- tgfβr1 injected embryos, with respect to controls ( Fig 1H and 1I ).…”

Section: Resultssupporting

confidence: 88%

“…Our data further support the previously reported role of TGF-β signaling in eye development. Its activity is required during optic cup formation, retinal pigment epithelium (RPE) and neural retina (NR) precursors specification, dorso-ventral patterning of the optic cup, retina proliferation and cell death [ 2 – 4 ] and axon guidance [ 34 ]. In this view, our findings demonstrate that TGF-β modulates miR-181a/b expression levels during a period of intense synapse formation in the visual system in order to define proper connectivity.…”

Section: Discussionmentioning

confidence: 99%

“…The concerted action of numerous cell-intrinsic and -extrinsic factors is required for retinal progenitor cell growth, elaboration of distinct neural cell types, spatial patterning, and axonal connectivity [ 1 ]. Among a number of evolutionarily conserved signaling pathways, the transforming growth factor-β (TGF-β) superfamily of secreted ligands are known to mediate important functions in the proliferation and cell death during retinal development [ 2 – 4 ]. However, there are indications of additional functions of TGF-β signaling in retinal patterning that remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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TGF-β Controls miR-181/ERK Regulatory Network during Retinal Axon Specification and Growth

et al. 2015

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Retinal axon specification and growth are critically sensitive to the dosage of numerous signaling molecules and transcription factors. Subtle variations in the expression levels of key molecules may result in a variety of axonal growth anomalies. miR-181a and miR-181b are two eye-enriched microRNAs whose inactivation in medaka fish leads to alterations of the proper establishment of connectivity and function in the visual system. miR-181a/b are fundamental regulators of MAPK signaling and their role in retinal axon growth and specification is just beginning to be elucidated. Here we demonstrate that miR-181a/b are key nodes in the interplay between TGF-β and MAPK/ERK within the functional pathways that control retinal axon specification and growth. Using a variety of in vivo and in vitro approaches in medaka fish, we demonstrate that TGF-β signaling controls the miR-181/ERK regulatory network, which in turn strengthens the TGF-β-mediated regulation of RhoA degradation. Significantly, these data uncover the role of TGF-β signaling in vivo, for the first time, in defining the correct wiring and assembly of functional retina neural circuits and further highlight miR-181a/b as key factors in axon specification and growth.

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Section: Resultssupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TGF-β Controls miR-181/ERK Regulatory Network during Retinal Axon Specification and Growth

et al. 2015

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“…The function of RBPMS in ganglion cells and the retina are unknown, although RBPMS interaction with Smad4 to influence TGF-b signaling suggests a role in retinal development and growth (Duenker, 2005;Wordinger and Clark, 2007). Consistent with this idea are findings that in mouse retina, a conditional Smad4 deletion results in alterations of RGC development and defects in the targeting of RGC axons to the optic nerve head (Murali et al, 2011). RBPMS2 mRNA (Gerber et al, 1999) and Hermes/RBPMS immunoreactivity (H€ ornberg et al, 2013) is expressed exclusively in RGCs including their axons and axonal terminals in embryonic Xenopus and zebrafish retina.…”

Section: Rbpms Expression In Rgcsmentioning

confidence: 86%

The RNA binding protein RBPMS is a selective marker of ganglion cells in the mammalian retina

Rodriguez

Müller

Brecha

2014

J of Comparative Neurology

421

419

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There are few neurochemical markers that reliably identify retinal ganglion cells (RGCs), which are a heterogeneous population of cells that integrate and transmit the visual signal from the retina to the central visual nuclei. We have developed and characterized a new set of affinity purified guinea pig and rabbit antibodies against RNA-binding protein with multiple splicing (RBPMS). On Western blots these antibodies recognize a single band at ~24 kDa, corresponding to RBPMS, and they strongly label RGC and displaced RGC (dRGC) somata in mouse, rat, guinea pig, rabbit and monkey retina. RBPMS immunoreactive cells and RGCs identified by other techniques have a similar range of somal diameters and areas. The density of RBPMS cells in mouse and rat retina is comparable to earlier semi-quantitative estimates of RGCs. RBPMS is mainly expressed in medium and large DAPI-, DRAQ5-, NeuroTrace- and NeuN-stained cells in the ganglion cell layer (GCL), and RBPMS is not expressed in syntaxin (HPC-1) immunoreactive cells in the inner nuclear layer (INL) and GCL, consistent with their identity as RGCs, and not displaced amacrine cells. In mouse and rat retina, most RBPMS cells are lost following optic nerve crush or transection at three weeks, and all Brn3a, SMI-32 and melanopsin immunoreactive RGCs also express RBPMS immunoreactivity. RBPMS immunoreactivity is localized to CFP-fluorescent RGCs in the B6.Cg-Tg(Thy1-CFP)23Jrs/J mouse line. These findings show that antibodies against RBPMS are robust reagents that exclusively identify RGCs and dRGCs in multiple mammalian species, and they will be especially useful for quantification of RGCs.

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“…BMPs are essential in retinal development, upregulated after retinal injury, and activated downstream Smad1 signaling is neuroprotective for RGC. [23][24][25][26][27][28] In addition, exogenous addition of BMP4 promotes the survival of RGC after NMDA-mediated damage, 28 but RGC axon regeneration has not been studied after BMP4/Smad1 activation. However, in a conditioning lesion, where the peripheral branch of the dorsal root ganglia (DRG) is axotomized, Smad1 signaling is induced and is required for the enhanced axon growth potential, while a central axotomy failed to activate Smad1.…”

mentioning

confidence: 99%

Activation of the BMP4/Smad1 Pathway Promotes Retinal Ganglion Cell Survival and Axon Regeneration

Thompson

Berry

Logan

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Citation: Thompson A, Berry M, Logan A, Ahmed Z. Activation of the BMP4/ Smad1 pathway promotes retinal ganglion cell survival and axon regeneration. Invest Ophthalmol Vis Sci. 2019;60:1748-1759. https://doi.org/ 10.1167 PURPOSE. We investigate if the BMP4/Smad1 intracellular signaling pathway is neuroprotective and axogenic in adult rodent retinal ganglion cells (RGC) in vivo and in vitro. METHODS.Adult retinal cultures were prepared from intact and after optic nerve crush (ONC) injured rats that have been stimulated to survive and regenerate using an intravitreal peripheral nerve (PN) graft. Laser capture microdissection (LCM) then was used to isolate RGC with and without neurites. Quantitative RT-PCR determined changes in BMP4/Smad1 signaling pathway mRNA. Immunohistochemistry confirmed localization of BMP4 and activation of Smad1 in ONCþPN-stimulated RGC in vivo. BMP4 peptide was used to stimulate RGC survival and neurite/axon regeneration in vitro and in vivo. Finally, the rapamycin sensitivity of the effects was determined in BMP4-stimulated RGC in vitro and in vivo. RESULTS.In retinal cultures prepared from intact and ONCþPN-stimulated rats, RGC with neurites had upregulated regeneration-related and BMP4/Smad1 signaling pathway mRNA levels, while low levels of these mRNAs were present in RGC isolated without neurites. An optimal dose of 200 ng/mL BMP4 peptide in vitro promoted approximately 30% RGC survival and disinhibited RGC neurite outgrowth, despite the presence of inhibitory CNS myelin extracts. BMP4 also promoted approximately 30% RGC survival in vivo and stimulated significant RGC axon regeneration at 100, 200, and 400 lm beyond the lesion site. Finally, the response of RGC to BMP4 treatment in vitro and in vivo was rapamycin-insensitive.CONCLUSIONS. Activation of the BMP4/Smad1 pathway promotes survival and axon regeneration independent of mTOR and, therefore, may be of therapeutic interest.

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Smad4 Is Required Predominantly in the Developmental Processes Dependent on the BMP Branch of the TGF-β Signaling System in the Embryonic Mouse Retina

Cited by 10 publications

References 57 publications

TGF-β Controls miR-181/ERK Regulatory Network during Retinal Axon Specification and Growth

TGF-β Controls miR-181/ERK Regulatory Network during Retinal Axon Specification and Growth

The RNA binding protein RBPMS is a selective marker of ganglion cells in the mammalian retina

Activation of the BMP4/Smad1 Pathway Promotes Retinal Ganglion Cell Survival and Axon Regeneration

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