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FMRP regulates the transition from radial glial cells to intermediate progenitor cells during neocortical development.
Open accessAbstract
During vertebrate cortical neurogenesis, radial glial cells (RGCs) serve as neural stem cells that generate neurons directly or indirectly through intermediate progenitor cells (IPCs). The transition from RGCs to IPCs is a key step in determining overall neuronal production and may underlie evolutionary expansion of the cerebral cortex. Here we show that this transition is controlled by fragile X mental retardation protein (FMRP), an RNA-binding protein whose deficiency causes fragile X syndrome. Analysis of mouse embryos electroporated with FMRP small hairpin RNA and knock-out mouse embryos lacking FMRP reveals that specific loss of FMRP causes depletion of neocortical RGCs due to an RGC-to-IPC cell fate change. The RGC depletion is associated with altered F-actin organization and can be largely rescued by overexpressing profilin 1 (Pfn1), a core actin regulatory protein promoting F-actin formation. Our data suggest that FMRP suppresses the transition from RGCs to IPCs during neocortical development by an actin-dependent mechanism.
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“Loss of FMRP-mediated translational control results in altered cell fate specification during early neural development (Tervonen et al., 2009; Saffary and Xie, 2011; Utami et al., 2020).”
From Astrocytes in fragile X syndrome (2024) · cites this paper as Saffary and Xie, 2011
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1 retracted
Fasano, C. A., Dimos, J. T., Ivanova, N. B., Lowry, N. A., Lemischka, I. R., & Temple, S. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.04.001 · Cited by 308 · cited 3×
“…have shown that functional compensation commonly occurs during development when the gene is constitutively deleted but not when the protein is acutely lost or inhibited (Deuel et al., 2006; Koizumi et al., 2006; Fasano et al., 2007; Satyanarayana and cortical neurogenesis than at later stages.”
BackgroundRetractedThe Glial Nature of Embryonic and Adult Neural Stem Cells
Kriegstein, A., & Alvarez-Buylla, A. (2009) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.051508.135600 · Cited by 2,475 · cited 6×
“The RGC-to-IPC transition, a key step in neuronal production from RGCs, may underlie the evolutionary expansion of the cerebral cortex (Fish et al., 2008; Kriegstein and Alvarez-Buylla, 2009).”
BackgroundInfluentialLifeact: a versatile marker to visualize F-actin
Riedl, J., Crevenna, A. H., Kessenbrock, K., Yu, J. H., Neukirchen, D., Bista, M., Bradke, F., Jenne, D., Holak, T. A., Werb, Z., et al. (2008) · Nature Methods · doi:10.1038/nmeth.1220 · Cited by 2,189 · cited 3×
“To overcome this problem, we used Lifeact-EGFP (Riedl et al., 2008, 2010), a fusion protein comprised of an F-actin binding domain and EGFP, to visualize the ring-like F-actin structure in transfected RGCs (Fig.”
BackgroundMethodFragile X Syndrome: Loss of Local mRNA Regulation Alters Synaptic Development and Function
Bassell, G. J., & Warren, S. T. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.004 · Cited by 1,051 · cited 6×
“The I304N mutation impairs the association of FMRP with RNA (Bassell and Warren, 2008) and renders the protein a null mutant (Zang et al., 2009).”
BackgroundInfluentialMammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms
Satyanarayana, A., & Kaldis, P. (2009) · Oncogene · doi:10.1038/onc.2009.170 · Cited by 800 · cited 4×
“Moreover, potential function of FMRP in RGCs may be masked in Fmr1 knock-out embryos by compensation, which often occurs in constitutive knock-out mice (Deuel et al., 2006; Koizumi et al., 2006; Fasano et al., 2007; Satyanarayana and Kaldis, 2009).”
BackgroundResultInfluentialGal, J. S., Morozov, Y. M., Ayoub, A. E., Chatterjee, M., RAKIC, P. T., & Haydar, T. F. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.4499-05.2006 · Cited by 358 · cited 2×
“Immediately following mCherry electroporation, EGFP should label cells with reduced levels of FMRP, because FMRP shRNA was coelectroporated with pCAX-EGFP 2 d before, and mCherry should label RGCs because in utero electroporation leads to specific transfection of RGCs (Gal et al., 2006).”
MethodThe fragile X mental retardation syndrome protein interacts with novel homologs FXR1 and FXR2.
Zhang, Y., O'Connor, J. P., Siomi, M. C., Srinivasan, S., Dutra, A., Nussbaum, R. L., & Dreyfuss, G. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb00220.x · Cited by 337 · cited 1×
“These three proteins have similar domain structures and interact with each other (Zhang et al., 1995).”
BackgroundLifeact mice for studying F-actin dynamics
Riedl, J., Flynn, K. C., Raducanu, A., Gärtner, F. C., Beck, G., Bösl, M. R., Bradke, F., Maßberg, S., Aszódi, A., Sixt, M., et al. (2010) · Nature Methods · doi:10.1038/nmeth0310-168 · Cited by 333 · cited 3×
“To overcome this problem, we used Lifeact-EGFP (Riedl et al., 2008, 2010), a fusion protein comprised of an F-actin binding domain and EGFP, to visualize the ring-like F-actin structure in transfected RGCs (Fig.”
BackgroundMethodSchenck, A., Bardoni, B., Langmann, C., Harden, N., Mandel, J.-L., & Giangrande, A. (2003) · Neuron · doi:10.1016/s0896-6273(03)00354-4 · Cited by 316 · cited 2×
“FMRP maintains the RGC pool by regulating the actin cytoskeleton Previous studies indicate that FMRP may regulate neuronal function by an actin-dependent mechanism (Schenck et al., 2003; Reeve et al., 2005).”
BackgroundDeuel, T. A., Liu, J. S.-H., Corbo, J. C., Yoo, S.-Y., Rorke-Adams, L. B., & Walsh, C. A. (2006) · Neuron · doi:10.1016/j.neuron.2005.10.038 · Cited by 291 · cited 5×
“Moreover, potential function of FMRP in RGCs may be masked in Fmr1 knock-out embryos by compensation, which often occurs in constitutive knock-out mice (Deuel et al., 2006; Koizumi et al., 2006; Fasano et al., 2007; Satyanarayana and Kaldis, 2009).”
BackgroundResultInfluential
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FMRP modulates neural differentiation through m6A-dependent mRNA nuclear export.
Edens, B. M., Vissers, C., Su, J., Arumugam, S., Xu, Z., Shi, H., Miller, N., Rojas Ringeling, F., Ming, G.-L., He, C., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.06.072 · Cited by 297
“…loss of Fmr1 has been associated with abnormalities in cortical development and dendritic spine formation, which may contribute to aberrant learning and behavior in fragile X syndrome (Castrén et al., 2005; La Fata et al., 2014; Saffary and Xie, 2011; Shen et al., 2019; Tervonen et al., 2009).”
Wen, T. H., Afroz, S., Reinhard, S. M., Palacios, A. R., Tapia, K., Binder, D. K., Razak, K. A., & Ethell, I. M. (2018) · Cerebral Cortex · doi:10.1093/cercor/bhx258 · Cited by 165
Neocortical neurogenesis and the etiology of autism spectrum disorder
Packer, A. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.03.002 · Cited by 138
Dynamic mRNA Transport and Local Translation in Radial Glial Progenitors of the Developing Brain
Pilaz, L., Lennox, A. L., Rouanet, J. P., & Silver, D. L. (2016) · Current Biology · doi:10.1016/j.cub.2016.10.040 · Cited by 139
FMRP regulates multipolar to bipolar transition affecting neuronal migration and cortical circuitry
Fata, G. L., Gärtner, A., Domıńguez-Iturza, N., Dresselaers, T., Dawitz, J., Poorthuis, R. B., Averna, M., Himmelreich, U., Meredith, R. M., Achsel, T., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3870 · Cited by 151
Inborn Errors of Long-Chain Fatty Acid β-Oxidation Link Neural Stem Cell Self-Renewal to Autism
Xie, Z., Jones, A. R., Deeney, J. T., Hur, S. K., & Bankaitis, V. A. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.01.004 · Cited by 122
“In utero electroporation was performed as described previously (Saffary and Xie, 2011).”
BackgroundMethodSelf-citationOf Men and Mice: Modeling the Fragile X Syndrome
Dahlhaus, R. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00041 · Cited by 133
“…was found to function in neuronal migration, differentiation and dendritic spine maturation (Hinton et al., 1991; Irwin et al., 2001; Saffary and Xie, 2011; Telias et al., 2013; La Fata et al., 2014; Khalfallah et al., 2017), it seems therefore possible that the microsatellite of FMR1 might…”
BackgroundPost-transcriptional regulation of mouse neurogenesis by Pumilio proteinsPreprint
Zhang, M., Chen, D., Xia, J., Han, W., Cui, X., Neuenkirchen, N., Hermes, G., Šestan, N., & Lin, H. (2017) · Genes & Development · doi:10.1101/gad.298752.117 · Cited by 111
“…et al. 2011; Chen et al. 2012), but their function in stem cell 1362 GENES & DEVELOPMENT maintenance has been demonstrated in the germline of only a few invertebrate species such as Drosophila, Caenorhabditis elegans, and the planarian Dugesia japonica (Parisi and Lin 2000; Salvetti et al. 2005).”
BackgroundNeural Progenitor Cell Polarity and Cortical Development
Arai, Y., & Taverna, E. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00384 · Cited by 112
“Loss-of-functions of FMR protein (FMRP) showed: (i) a switch from AP to BP fate, indicating the depletion of aRGCs pool (Saffary and Xie, 2011); (ii) defects in neuronal positioning due to the misregulation of Frontiers in Cellular Neuroscience | www.frontiersin.org 7 December 2017 | Volume 11 |…”
BackgroundTrajectories of Early Brain Volume Development in Fragile X Syndrome and Autism
Hazlett, H. C., Poe, M. D., Lightbody, A. A., Styner, M. A., MacFall, J. R., Reiss, A. L., & Piven, J. (2012) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2012.07.003 · Cited by 102
Kraushar, M. L., Thompson, K., Wijeratne, H. R. S., Viljetic, B., Sakers, K., Marson, J. W., Kontoyiannis, D. L., Buyske, S., Hart, R. P., & Rasin, M.-R. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1408305111 · Cited by 98
RNA on the brain: emerging layers of post‐transcriptional regulation in cerebral cortex development
Lennox, A. L., Mao, H., & Silver, D. L. (2017) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.290 · Cited by 73
Casingal, C. R., Kikkawa, T., Inada, H., Sasaki, Y., & Osumi, N. (2020) · Molecular Brain · doi:10.1186/s13041-020-00706-1 · Cited by 70
Post‐transcriptional regulation in corticogenesis: how RNA‐binding proteins help build the brain
Pilaz, L., & Silver, D. L. (2015) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1289 · Cited by 72
CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size
Ludwig, A. L., Espinal, G., Pretto, D. I., Jamal, A., Arqué, G., Tassone, F., Berman, R. F., & Hagerman, P. J. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu032 · Cited by 70
“P0), consistent with the critical role of FMRP in brain development (49,58), followed by what appears to be a general pattern of decline with age.”
BackgroundThe role of Pax6 in brain development and its impact on pathogenesis of autism spectrum disorder
Kikkawa, T., Casingal, C. R., Chun, S. H., Shinohara, H. M., Hiraoka, K., & Osumi, N. (2018) · Brain Research · doi:10.1016/j.brainres.2018.02.041 · Cited by 67
Castrén, M. L., & Ċastrén, E. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.05.018 · Cited by 68
“…abnormalities in the early development in FXS, including abnormal differentiation of neural progenitor cells (NPCs) and impaired migration of newly born neurons (Castrén et al., 2005; Tervonen et al., 2009; Callan and Zarnescu, 2011; Saffary and Zhigang, 2011; Sheridan et al., 2011; Castren, 2012).”
Boland, M. J., Nazor, K. L., Tran, H. T. T., Szűcs, A. L., Lynch, C. L., Paredes, R., Tassone, F., Sanna, P. P., Hagerman, R. J., & Loring, J. F. (2017) · Brain · doi:10.1093/brain/aww357 · Cited by 67
“Moreover, studies have shown that neuronal progenitor cells of Fmr1 knockout mice exhibit aberrant migration and differentiation (Castren et al., 2005; Tervonen et al., 2009; Saffary and Xie, 2011).”
BackgroundTranslating neural stem cells to neurons in the mammalian brain
Zahr, S. K., Kaplan, D. R., & Miller, F. D. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-019-0411-9 · Cited by 67
Ding, W. Y., Huang, J., & Wang, H. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1008653 · Cited by 65
What we can learn from a genetic rodent model about autism
Möhrle, D., Fernández, M. C., Peñagarikano, O., Frick, A., Allman, B. L., & Schmid, S. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.12.015 · Cited by 60
Mao, X., An, Q., Xi, H., Yang, X.-J., Zhang, X., Yuan, S., Wang, J., Hu, Y., Liu, Q., & Fan, G. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2019.08.012 · Cited by 57
“The adhesion molecule PCDH9 and cytoskeletal proteins PFN1 and TMSB10, molecules involved in the balance of NSC quiescence and activation, were also specifically expressed in these RPCs (Morizur et al., 2018; Saffary and Xie, 2011) (Figure 4E).”
Ochi, S., Manabe, S., Kikkawa, T., & Osumi, N. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116115 · Cited by 62
“A knockdown of Fmr1 and Fmr1 knock-out mice resulted in a reduction in the size of the Pax6+ NSC pool due to an NSCto-IPC cell fate change [110].”
BackgroundConcise Review: Fragile X Proteins in Stem Cell Maintenance and Differentiation
Li, Y., & Zhao, X. (2014) · Stem Cells · doi:10.1002/stem.1698 · Cited by 57
Achuta, V. S., Möykkynen, T. P., Peteri, U., Turconi, G., Rivera, C., KEINÄNEN, K. P., & Castrén, M. L. (2018) · Science Signaling · doi:10.1126/scisignal.aan8784 · Cited by 52
“Altered differentiation of FXS iPSC-derived neural progenitors to glutamatergic lineages is consistent with impaired maturation of glutamatergic neurons and their signaling identified during the development of the Fmr1-KO mouse brain (1, 13, 14).”
BackgroundRaj, N., McEachin, Z. T., Harousseau, W., Zhou, Y., Zhang, F., Merritt-Garza, M. E., Taliaferro, J. M., Kalinowska, M., Marro, S. G., Hales, C. M., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108991 · Cited by 54
“Some mRNA targets of FMRP are known to mediate cell proliferation and neurogenesis (Luo et al., 2010), and FMRP deficiency in murine neural stem cells disrupts translation and neuronal differentiation (Liu et al., 2018; Saffary and Xie, 2011).”
Hyperexcitability and homeostasis in fragile X Syndrome.
Liu, X., Kumar, V., Tsai, N.-P., & Auerbach, B. D. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.805929 · Cited by 53
“FMRP expression is also developmentally regulated in both humans (Abitbol et al., 1993) and mice (Saffary and Xie, 2011), with expression starting at early embryonic stages, peaking during early post-natal developmental critical periods, but remaining at sustained levels throughout adulthood (Till,…”
BackgroundSolozobova, V., Wyvekens, N., & Pruszak, J. (2012) · Stem Cell Reviews and Reports · doi:10.1007/s12015-012-9381-8 · Cited by 54
“In addition, via direct linkage to cytoskeletal components integrin and cadherin signaling can also lead to modulation of a variety of actin-regulated and other mechanotransductory pathways [140–143].”
BackgroundDeBoer, E., Kraushar, M. L., Hart, R. P., & Rašin, M. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.05.042 · Cited by 47
“However, oRG will self renew and give rise to neural progenies and IPCs.”
BackgroundResultInfluentialTranscriptional and Post-Transcriptional Mechanisms of the Development of Neocortical Lamination
Popovitchenko, T., & Rašin, M. (2017) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2017.00102 · Cited by 45
“It was first posited that FMRP interacts with cytoskeleton proteins in RG (Saffary and Xie, 2011).”
BackgroundAchuta, V. S., Grym, H., Putkonen, N., Louhivuori, V., Kärkkäinen, V., Koıstınaho, J., Roybon, L., & Castrén, M. L. (2016) · Developmental Neurobiology · doi:10.1002/dneu.22419 · Cited by 46
“A reduced pool of radial glia and an increased number of Tbr2-positive basal progenitors are shown in the embryonic cortex of Fmr1-KO mice (Castren et al., 2005; Tervonen, et al., 2009; Saffary and Xie, 2011).”
BackgroundKhalfallah, O., Jarjat, M., Davidovic, L., Nottet, N., Cestèle, S., Mantegazza, M., & Bardoni, B. (2016) · Stem Cells · doi:10.1002/stem.2505 · Cited by 46
Harrison, S. J., Nishinakamura, R., Jones, K. R., & Monaghan, A. P. (2011) · Disease Models & Mechanisms · doi:10.1242/dmm.002873 · Cited by 42
“Disruption of Notch or Fragile-X mental retardation protein signaling promotes the transition of RGCs to IPCs (Mizutani et al., 2007; Saffary and Xie, 2011; Yoon et al., 2008).”
BackgroundTranscriptional regulation of intermediate progenitor cell generation during hippocampal development
Harris, L., Zalucki, O. H., Gobius, I., McDonald, H., Osinki, J., Harvey, T. J., Essebier, A., Vidovic, D., Gladwyn-Ng, I. E., Burne, T. H. J., et al. (2016) · Development · doi:10.1242/dev.140681 · Cited by 41
“DISCUSSION Studies have begun to reveal the factors that drive the progression of radial glia into IPCs during development (Farkas et al., 2008; Sessa et al., 2008; Saffary and Xie, 2011).”
BackgroundSerotonin dysregulation in Fragile X Syndrome: implications for treatment
Hanson, A. C., & Hagerman, R. J. (2014) · Intractable & Rare Diseases Research · doi:10.5582/irdr.2014.01027 · Cited by 40
“For example, FMRP is thought to play a crucial role in maintenance of radial glial cells (RGCs) in the neocortex during early development (53).”
Heads‐up: New roles for the fragile X mental retardation protein in neural stem and progenitor cells
Callan, M. A., & Zarnescu, D. C. (2011) · genesis · doi:10.1002/dvg.20745 · Cited by 39
“…the previously mentioned studies on FMRP’s role in neurogenesis were performed using embryonic or early postnatal day brains (Castren et al., 2005; Saffary and Xie, 2011; Tervonen et al., 2009), Luo et al. set out to test the role of FMRP in adult neural progenitors, particularly within the…”
BackgroundInfluentialMaking Ramón y Cajal proud: Development of cell identity and diversity in the cerebral cortex
Bella, D. J. D., Domıńguez-Iturza, N., Brown, J. R., & Arlotta, P. (2024) · Neuron · doi:10.1016/j.neuron.2024.04.021 · Cited by 40
Callan, M. A., Clements, N., Ahrendt, N., & Zarnescu, D. C. (2012) · Brain Research · doi:10.1016/j.brainres.2012.03.042 · Cited by 38
“Loss of function approaches have shown that in the developing brain, FMRP inhibits the transition from a stem cell-like to an intermediate progenitor fate (Saffary and Xie, 2011).”
Boucherie, C., Boutin, C., Jossin, Y., Schakman, O., Goffinet, A. M., Ris, L., Gailly, P. L., & Tissir, F. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.236 · Cited by 37
MicroRNA-129 modulates neuronal migration by targeting Fmr1 in the developing mouse cortex
Wu, C., Zhang, X., Chen, P., Ruan, X., Liu, W., Li, Y., Sun, C., Hou, L., Yin, B., Qiang, B., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1517-1 · Cited by 42
Fragile X related protein 1 (FXR1P) regulates proliferation of adult neural stem cells
Patzlaff, N. E., Nemec, K. M., Malone, S. G., Li, Y., & Zhao, X. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx034 · Cited by 34
Profilin Isoforms in Health and Disease – All the Same but Different
Murk, K., Ornaghi, M., & Schiweck, J. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.681122 · Cited by 38
“…in Drosophila indicate a negative role of FMRP in regulating profilin expression, studies in mice came to opposite conclusions: overexpression of PFN1 in radial glial cells largely rescues developmental defects during corticogenesis in FMRP-depleted mice (Figure 6.5; Saffary and Xie, 2011).”
BackgroundInfluentialPilaz, L., & Silver, D. L. (2017) · FEBS Letters · doi:10.1002/1873-3468.12626 · Cited by 31
FMRP Regulates Neurogenesis In Vivo in Xenopus laevis Tadpoles
Faulkner, R. L., Wishard, T. J., Thompson, C. K., Liu, H.-H., & Cline, H. T. (2014) · eNeuro · doi:10.1523/eneuro.0055-14.2014 · Cited by 33
“Cell survival was unaffected in Drosophila dFmr1 mutant neuroblast cultures and following acute FMRP knockdown in vivo in embryonic mouse cortex (Callan et al., 2010; Saffary and Xie, 2011).”
BackgroundInfluentialDecoding mixed messages in the developing cortex: translational regulation of neural progenitor fate
Hoye, M. L., & Silver, D. L. (2020) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2020.10.001 · Cited by 34
“Some RBPs, such as FMRP, may dually function as both translational activators and repressors to influence neurogenesis, depending upon the species [54,55].”
Backgroundvan Blitterswijk, M., Baker, M., Bieniek, K. F., Knopman, D. S., Josephs, K. A., Boeve, B. F., Caselli, R. J., Wszołek, Z. K., Petersen, R. C., Graff‐Radford, N. R., et al. (2013) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.3109/21678421.2013.787630 · Cited by 30
Pinar, C., Yau, S., Sharp, Z., Shamei, A., Fontaine, C. J., Meconi, A., Lottenberg, C. P., & Christie, B. R. (2018) · Brain Plasticity · doi:10.3233/bpl-170052 · Cited by 28
“35 Fragile X mental retardation protein (FMRP) is a 36 mRNA binding protein thought to be important for 37 normal neuronal development [6, 7].”
BackgroundAgrawal, M., & Welshhans, K. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.717170 · Cited by 25
“Additionally, overexpression of Cyclin D2 leads to an increase in the number of neural progenitor cells, thus confirming its role in neurogenesis (Saffary and Xie, 2011; Tsunekawa et al., 2012).”
BackgroundLocal gene regulation in radial glia: Lessons from across the nervous system
D’Arcy, B. R., & Silver, D. L. (2020) · Traffic · doi:10.1111/tra.12769 · Cited by 22
“A similar role for the endosome pathway has been described in fungi, suggesting that this mechanism may be evolutionarily conserved.60,61 Indeed, it is possible that endosome and vesicle dependent translation hot spots could occur in mammalian RGCs. Mitochondria have been observed in RGC basal structures, but roles fo…”
BackgroundInfluentialAbnormal Levels of Gadd45alpha in Developing Neocortex Impair Neurite Outgrowth
Sarkisian, M. R., & Siebzehnrubl, D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044207 · Cited by 24
The role and regulatory mechanism of m6A methylation in the nervous system
Jiang, L., Li, X., Wang, S., Yuan, Z., & Cheng, J. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.962774 · Cited by 26
“Another study reported that deletion of Fmr1 is associated with abnormalities in cortical development and dendritic spine formation, which leads to abnormal learning and behavior in fragile X syndrome (Castrén et al., 2005; Saffary and Xie, 2011; La Fata et al., 2014).”
BackgroundBankaitis, V. A., & Xie, Z. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.aw119.008137 · Cited by 24
“Second, the traditional ASD-linked genes/pathways (Wnt, PTEN, TSC1/TSC2, FMR1) also impinge on NSC self-renewal and differentiation during development (18-21), although these activities in the context of NSC biology are largely ignored in contemporary discussions of mechanisms of ASD”
BackgroundSelf-citationJeon, S. J., Kim, J., Kim, K. C., Han, S. M., Go, H. S., Seo, J. E., Choi, C. S., Ryu, J. H., Shin, C. Y., & Song, M. (2013) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-013-0014-9 · Cited by 23
“While many researchers reported the altered neural stem cell proliferation and differentiation in embryonic and adult brains of Fmr1 KO mice, the mechanistic studies how FMRP modulate stem cell proliferation and differentiation are far from exhaustive (Castren et al. 2005; Tervonen et al. 2009; Saffary and Xie 2011).”
BackgroundGuo, Y., Chen, X., Xing, R., Wang, M., Zhu, X., & Guo, W. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx417 · Cited by 23
“1F and G), which might not be owing to the effects of FMRP deficiency on extended trailing processes/axon formation during brain development (22,23).”
Kou, Z., Mo, J., Wu, K., Qiu, M., Huang, Y., Tao, F., Yu, L., Lv, L., & Sun, F. (2019) · Glia · doi:10.1002/glia.23609 · Cited by 22
“…Caille, Lim, GarciaVerdugo, & Alvarez-Buylla, 1999; Gotz, Sirko, Beckers, & Irmler, 2015; Huang & Tan, 2015; Merkle, Tramontin, Garcia-Verdugo, & AlvarezBuylla, 2004) and pathological conditions (Duan et al., 2015; Mo et al., 2018; Pan, Mao, & Sun, 2017; Saffary & Xie, 2011; Shen et al., 2016).”
Achuta, V. S., Rezov, V., Uutela, M., Louhivuori, V., Louhivuori, L., & Castrén, M. L. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.3753-13.2014 · Cited by 22
Making sense of mRNA landscapes: Translation control in neurodevelopment
Park, Y., Page, N. F., Salamon, I., Li, D., & Rašin, M. (2021) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1674 · Cited by 22
“…and promoting radial migration, dendrite and dendritic spine development, circuit function, and plasticity (Cunningham et al., 2011; De Rubeis et al., 2013; Goncalves et al., 2013; Hays et al., 2011; La Fata et al., 2014; Nagaoka et al., 2016; Saffary & Xie, 2011; Tervonen et al., 2009).”
BackgroundThe Role of Dynamic miRISC During Neuronal Development
Nawalpuri, B., Ravindran, S., & Muddashetty, R. S. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.00008 · Cited by 19
Increasing our understanding of human cognition through the study of fragile X syndrome
Cook, D., Nuro, E., & Murai, K. K. (2013) · Developmental Neurobiology · doi:10.1002/dneu.22096 · Cited by 22
“…shown to alter cortical plate development by affecting both the transition from radial glial cells to intermediate precursor cells and the differentiation of excitatory glutamatergic cells (Tervonen et al., 2009; Saffary and Xie, 2011), offering further support for the role of FMRP in neurogenesis.”
BackgroundRegulation of Adult Neurogenesis by the Fragile X Family of RNA Binding Proteins
Patzlaff, N. E., Shen, M., & Zhao, X. (2017) · Brain Plasticity · doi:10.3233/bpl-170061 · Cited by 18
“When FMRP was down-regulated, the number of radial glia cells was depleted by the increasing rate of this transition [182].”
BackgroundFunctional implications of hippocampal adult neurogenesis in intellectual disabilities
Pons‐Espinal, M., de Lagrán, M. M., & Dierssen, M. (2013) · Amino Acids · doi:10.1007/s00726-013-1489-x · Cited by 18
“5–17.5 In vivo Promoted a shift from neocortical RGC to IPC (Saffary and Xie 2011) FXS Human fetuses (18 w) In vitro Increased neurons and reduced glia cells from hNSCs (Castren et al. 2005) FXS Human fetuses (14 w) In vitro No differences in proliferation and neuronal differentiation of hNSCs (Bhattacharyya et al. 20…”
BackgroundInfluentialSpencer, K. B., Mulholland, P. J., & Chandler, L. J. (2016) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.13060 · Cited by 17
“While the importance of FMRP during development has been well established, a potential role for FMRP in mediating alterations in translation in response to chronic EtOH exposure is not known (Bonaccorso et al., 2015; Fernandez et al., 2013; Saffary and Xie, 2011).”
Kullmann, J. A., Meyer, S., Pipicelli, F., Kyrousi, C., Schneider, F., Bartels, N., Cappello, S., & Rust, M. B. (2019) · Cerebral Cortex · doi:10.1093/cercor/bhz321 · Cited by 16
FMRP ribonucleoprotein complexes and RNA homeostasis
Suardi, G. A. M., & Haddad, L. A. (2020) · Advances in genetics · doi:10.1016/bs.adgen.2020.01.001 · Cited by 18
RNA-binding protein research with transcriptome-wide technologies in neural development
Yano, M., Ohtsuka, T., & Okano, H. (2014) · Cell and Tissue Research · doi:10.1007/s00441-014-1923-8 · Cited by 16
Weisz, E. D., Monyak, R. E., & Jongens, T. A. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.05.015 · Cited by 16
The RNA-binding protein MARF1 promotes cortical neurogenesis through its RNase activity domain
Kanemitsu, Y., Fujitani, M., Fujita, Y., Zhang, S., Su, Y., Kawahara, Y., & Yamashita, T. (2017) · Scientific Reports · doi:10.1038/s41598-017-01317-y · Cited by 18
Meyerink, B. L., Pratiksha, K. C., Tiwari, N. K., Kittock, C. M., Klein, A. K., Evans, C. M., & Pilaz, L. (2022) · Development · doi:10.1242/dev.200616 · Cited by 14
Danesi, C., KEINÄNEN, K. P., & Castrén, M. L. (2019) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2019.00002 · Cited by 12
“CP-AMPARs provide an important route for Ca2+ entry into progenitors, and changes of Ca2+ signaling can contribute to altered fate determination, differentiation, and migration of FXS neural progenitors (Castren et al., 2005; Tervonen et al., 2009; Saffary and Xie, 2011; Sheridan et al., 2011; Liu et al., 2012; Doers…”
BackgroundTranslational Control during Mammalian Neocortex Development and Postembryonic Neuronal Function
Oliveira, N. C. M., Lins, É. M., Massirer, K. B., & Bengtson, M. H. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.09.006 · Cited by 11
D’Antoni, S., Spatuzza, M., Bonaccorso, C. M., & Catania, M. V. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105731 · Cited by 11
“FMRP is also present at high levels in radial glial cells (RGCs) of the embryonic mouse neocortex, where it controls mRNAs transport and localization (Pilaz et al., 2016).”
InfluentialOrchestrating Neural Development Through mRNA Translation Regulation
Rodrigue, B., Sajish, M., Salmaso, N., & Aguilar‐Valles, A. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70128 · Cited by 10
“5 showed a severe depletion in the total pool of RGCs (Saffary and Xie 2011).”
InfluentialNeocortical development as an evolutionary platform for intragenomic conflict
Lewitus, É., & Kalinka, A. T. (2013) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2013.00002 · Cited by 9
“Saffary and Xie (2011) recently showed that FMR1 utilizes an actin-dependent mechanism to control the ratio of radial glia (RG) and intermediate progenitor cells (IPs) during neurogenesis, suggesting that the observed increase in neurons is due to a shift in the relative ratio of RG to IPs during…”
BackgroundProtein Synthesis and Translational Control in Neural Stem Cell Development and Neurogenesis
Mohammad, L., Wiseman, J., Erickson, S. E., & Yang, G. (2019) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780190686307.013.21 · Cited by 8
Astrocytes in fragile X syndrome
Talvio, K., & Castrén, M. L. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1322541 · Cited by 8
Regulation of mRNA translation in stem cells; links to brain disorders
Statoulla, E., Chalkiadaki, K., Karozis, D., & Gkogkas, C. G. (2021) · Cellular Signalling · doi:10.1016/j.cellsig.2021.110166 · Cited by 8
Sungur, A. Ö., Zeitouny, C., Gabele, L., Metz, I., Wöhr, M., Michaelsen‐Preusse, K., & Rust, M. B. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.952782 · Cited by 7
“Interestingly, profilin1 acts downstream of the fragile X mental retardation protein state FMRP in neural progenitors (Saffary and Xie, 2011) and profilin1, as well as its Drosophila homolog chickadee, but not profilin2 have been implicated in the cellular defects of fragile X syndrome (FXS) pathology (Reeve et al.”
BackgroundPosttranscriptional and translational control of neurogenesis
Alsina, F. C., & Silver, D. L. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-814405-3.00028-x · Cited by 6
Osumi, N., & Kikkawa, T. (2013) · Springer eBooks · doi:10.1007/978-4-431-54496-8_3 · Cited by 8
The role of brain-derived neurotrophic factor in neural circuit development and function
Autry, A. E., & Bambah-Mukku, D. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-823672-7.00020-x · Cited by 6
Avraham, O., Deng, P., Maschi, D., Klyachko, V. A., & Cavalli, V. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.796070 · Cited by 5
FMRP Regulates Neurogenesis In Vivo in Xenopus laevis Tadpoles
Faulkner, R. L., Wishard, T. J., Thompson, C. K., Liu, H.-H., & Cline, H. T. (2015) · eNeuro · doi:10.1523/eneuro.0055-14.2015 · Cited by 5
Extrinsic Regulators of mRNA Translation in Developing Brain: Story of WNTs
Park, Y., Lofton, M., Li, D., & Rašin, M. (2021) · Cells · doi:10.3390/cells10020253 · Cited by 3
“FMRP represses the RGC to IP transition, maintaining RGCs in an undifferentiated state [52].”
BackgroundA Transcriptomic Dataset of Embryonic Murine Telencephalon of Fmr1-Deficient Mice
Ebrahimiazar, S., Kikkawa, T., Minakuchi, Y., Miyashita, S., Manabe, S., Hoshino, M., Toyoda, A., & Osumi, N. (2025) · Scientific Data · doi:10.1038/s41597-025-05104-7 · Cited by 2
Pacey, L. K. K. (2013) · Journal of Stem Cell Research & Therapy · doi:10.4172/2157-7633.s12-001 · Cited by 1
“Specific examples of FMRP control include regulation of the transition from the radial glial cell to the intermediate progenitor [26] and the regulation of olfactory bulb neuron differentiation [27].”
BackgroundUnderstanding pathophysiology in fragile X syndrome: a comprehensive review
Juárez, J. C. C., Gómez, A. A., Díaz, A. E. S., & Arévalo, G. S. (2024) · Neurogenetics · doi:10.1007/s10048-024-00794-4 · Cited by 1
“Saffary et al. found that the loss of FMRP tend to increase the differentiation rate of the radial glial cells (RGCs) into intermediate progenitor cells (IPCs), leading to a significant reduction in RGCs [55].”
Regulation of m RNA Localization and Translation in Brain Development
Kikkawa, T., Naher, S., & Osumi, N. (2023) · Wiley eBooks · doi:10.1002/9781119860914.ch29 · Cited by 1
Variabilidade do domínio KH-2 da proteína do retardo mental do X frágil (FMRP)
Velloso, F. J. (2013) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.41.2013.tde-21032014-090729
Corrêa, J. D. C. (2014) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.41.2014.tde-01092014-085006
Molecular mechanisms involved in altered differentiation of neural progenitors in Fragile X Syndrome
Achuta, V. S. (2018) · Työväentutkimus Vuosikirja
Profilin isoforms in the hippocampus in health and disease
Zessin, S. (2014) · Digitale Bibliothek Braunschweig (Verbundzentrale Göttingen (VZG)) · doi:10.24355/dbbs.084-201501221125-0
Casingal, C. R., Kikkawa, T., Inada, H., & Osumi, N. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/769026 · Cited by 1
“This is quite reasonable because FMRP has been shown to play an important role in maintaining the RGCs, i.e., the main source of neurons during brain development (Saffary and Xie, 2011; Götz and Barde, 2005).”
BackgroundResultInfluentialKiebler, M. A., Moya, S. M. F., & Ehses, J. (2017) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.727072594.793538406
Fmr1 exon 14 skipping in late embryonic development of the rat forebrain
Corrêa-Velloso, J. C., Linardi, A., Glaser, T., Velloso, F. J., Rivas, M. P., Leite, R. E. P., Grinberg, L. T., Ulrich, H., Akins, M. R., Chiavegatto, S., et al. (2022) · BMC Neuroscience · doi:10.1186/s12868-022-00711-1 · Cited by 1
“During cerebral corticogenesis of the mouse embryo, loss of Fmrp depletes radial glia cells by increasing their differentiation into intermediate progenitor cells [19], and affects the multipolar to bipolar neuronal transition in the cortical plate [20].”
BackgroundCharacterization of proneural bHLH transcription factor target genes in X. laevis
Essel, E. A. (2022) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-9453
Wiśniewska, K., Żabińska, M., Gaffke, L., Szulc, A., Walter, B. M., Węgrzyn, G., & Pierzynowska, K. (2024) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2912415
“However, overexpression of PFN1 can correct developmental defects during corticogenesis in these mice [19,32,33].”
Abnormal regulation of membrane-less organelles contributes to profilin1-associated ALS
Ma, G., Ruan, X., Yang, B., Li, N., Su, D., Sun, S., Chen, S., Xu, K., Ying, Z., & Wang, H. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110259
“Moreover, PFN1 expression is reduced in FMRP-depleted mice, a classical disease model related to Fragile-X syndrome (FXS), and overexpression of PFN1 can signi fi - cantly rescue the developmental defects in this disease model (18 – 20).”
Additional file 1 of Fmr1 exon 14 skipping in late embryonic development of the rat forebrain
Corrêa-Velloso, J. C., Linardi, A., Glaser, T., Velloso, F. J., Rivas, M. P., Leite, R. E. P., Grinberg, L. T., Ulrich, H., Akins, M. R., Chiavegatto, S., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19947736
Study of Exon Junction Complex in mouse neural stem cells
Mishra, R. (2016) · theses.fr (ABES) · doi:10.70675/763ca66az53efz4562zb337z755d833bb64d
Metadata
- Authors
- Saffary, R., & Xie, Z.
- Affiliations
- Boston Medical Center (US)
- Boston University (US)
- Corresponding author
- Xie, Zhigang
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-01-26
- Volume
- 31
- Issue
- 4
- Pages
- 1427-1439
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6623593
- OpenAlex
- W2082366834
- Cited by
- 103
- References
- 31
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 5 · 2023: 1 · 2022: 9 · 2021: 6 · 2020: 9 · 2019: 11 · 2018: 5 · 2017: 13 · 2016: 8 · 2015: 3 · 2014: 10 · 2013: 11 · 2012: 4
- FWCI
- 2.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Keywords
- FMRP, fragile X syndrome, radial glia, intermediate progenitor cells, cortical neurogenesis, neocortex development, cell fate transitions, actin cytoskeleton, F-actin organization, profilin-1, RNA-binding proteins, cerebral cortex evolution
- MeSH terms
- Actins, Animals, Neuroglia, Mice, Knockout, Neocortex, RNA, Small Interfering, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, Neurogenesis, Neural Stem Cells
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