The Role of Smad Proteins for Development, Differentiation and Dedifferentiation of Neurons

Ueberham, Uwe; Arendt, Thomas

doi:10.5772/54532

Cited by 10 publications

(12 citation statements)

References 241 publications

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“…The Smad3 control of proliferation is crucial during earlypostnatal differentiation of cerebellar neurons into postmitotic neurons, by activation of cyclin-dependent kinase inhibitors p21, p27 and markers of neuronal differentiation (Ueberham and Arendt, 2013). A clear inhibitory function of Smad3 on neural progenitors proliferation was observed in chickens developing a spinal cord, where Smad3 also promotes differentiation of selected neurons and glia (Garcia-Campmany and Marti, 2007).…”

Section: Discussionmentioning

confidence: 98%

A Smad3 transgenic reporter reveals TGF-beta control of zebrafish spinal cord development

Casari

Schiavone

Facchinello

et al. 2014

Developmental Biology

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TGF-beta (TGFβ) family mediated Smad signaling is involved in mesoderm and endoderm specifications, left-right asymmetry formation and neural tube development. The TGFβ1/2/3 and Activin/Nodal signal transduction cascades culminate with activation of SMAD2 and/or SMAD3 transcription factors and their overactivation are involved in different pathologies with an inflammatory and/or uncontrolled cell proliferation basis, such as cancer and fibrosis. We have developed a transgenic zebrafish reporter line responsive to Smad3 activity. Through chemical, genetic and molecular approaches we have seen that this transgenic line consistently reproduces in vivo Smad3-mediated TGFβ signaling. Reporter fluorescence is activated in phospho-Smad3 positive cells and is responsive to both Smad3 isoforms, Smad3a and 3b. Moreover, Alk4 and Alk5 inhibitors strongly repress the reporter activity. In the CNS, Smad3 reporter activity is particularly high in the subpallium, tegumentum, cerebellar plate, medulla oblongata and the retina proliferative zone. In the spinal cord, the reporter is activated at the ventricular zone, where neuronal progenitor cells are located. Colocalization methods show in vivo that TGFβ signaling is particularly active in neuroD+ precursors. Using neuronal transgenic lines, we observed that TGFβ chemical inhibition leads to a decrease of differentiating cells and an increase of proliferation. Similarly, smad3a and 3b knock-down alter neural differentiation showing that both paralogues play a positive role in neural differentiation. EdU proliferation assay and pH3 staining confirmed that Smad3 is mainly active in post-mitotic, non-proliferating cells. In summary, we demonstrate that the Smad3 reporter line allows us to follow in vivo Smad3 transcriptional activity and that Smad3, by controlling neural differentiation, promotes the progenitor to precursor switch allowing neural progenitors to exit cell cycle and differentiate.

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Section: Discussionmentioning

confidence: 98%

A Smad3 transgenic reporter reveals TGF-beta control of zebrafish spinal cord development

Casari

Schiavone

Facchinello

et al. 2014

Developmental Biology

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“…3D derivation of human astrocytes from human iPSCs (hiPSCs) mimics in vivo development by mirroring temporal signaling pathways within stages of embryonic and perinatal development (Chambers et al, 2009;Huang et al, 2016;Klum et al, 2018;Matuzelski et al, 2017;Stolt & Wegner, 2010). By inhibiting various signaling receptors within the transforming growth factor beta (TGFb) signaling pathway and BMP pathway, pluripotent stem cells are guided toward neural induction and the subsequent expression of SOX1 and PAX6, resulting in populations of multipotent neural progenitors or neural precursor cells (NPCs;Neely et al, 2012;Ueberham, 2013). This technique is often referred to as dual SMAD inhibition.…”

Section: D Derivation Of Human Astrocytesmentioning

confidence: 99%

An update on human astrocytes and their role in development and disease

Majo

Koontz

Rowitch

et al. 2020

Glia

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Human astrocytes provide trophic as well as structural support to the surrounding brain cells. Furthermore, they have been implicated in many physiological processes important for central nervous system function. Traditionally astrocytes have been considered to be a homogeneous class of cells, however, it has increasingly become more evident that astrocytes can have very different characteristics in different regions of the brain, or even within the same region. In this review we will discuss the features of human astrocytes, their heterogeneity, and their generation during neurodevelopment and the extraordinary progress that has been made to model these fascinating cells in vitro, mainly from induced pluripotent stem cells. Astrocytes' role in disease will also be discussed with a particular focus on their role in neurodegenerative disorders. As outlined here, astrocytes are important for the homeostasis of the central nervous system and understanding their regional specificity is a priority to elucidate the complexity of the human brain.

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“…6E). Smad1 protein is known to be constantly degraded in the cytosol through its phosphorylation on the linker region by Glycogen synthase kinase 3 (GSK-3β) or Mitogen-activated protein kinase (MAPK) (Wnt/FGF signaling components), followed by polyubiquitylation (Fuentealba et al, 2007;Ueberham and Arendt, 2013). So, we examined the amount of Smad proteins present when Fam46a was expressed, to evaluate whether Fam46a is involved in this process.…”

Section: Fam46a Activates Bmp Signaling Via the Stabilization Of Smad1mentioning

confidence: 99%

“…7C,E). Smad1 protein is known to be constantly degraded in the cytosol through phosphorylation in its linker region by GSK-3β or MAPK (Wnt/FGF signaling components), followed by polyubiquitylation (Fuentealba et al, 2007;Ueberham and Arendt, 2013). It is possible that the binding of Fam46a with Smad1-MH1 and linker region in the cytosol causes the inhibition of Smad1 phosphorylation and subsequent degradation, and that the stabilization of Smad1 promotes the activation of BMP signaling.…”

Section: The Molecular Function Of Fam46a In Bmp Signaling Activationmentioning

confidence: 99%

Fam46a regulates BMP-dependent pre-placodal ectoderm differentiation in Xenopus

et al. 2018

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The pre-placodal ectoderm (PPE) is a specialized ectodermal region which gives rise to the sensory organs and other systems. The PPE is induced from the neural plate border during neurulation, but the molecular mechanism of PPE formation is not fully understood. In this study, we examined the role of a newly identified PPE gene, Fam46a, during embryogenesis. Fam46a contains a nucleoside triphosphate transferase domain, but its function in early development was previously unclear. We show that Fam46a is expressed in the PPE in Xenopus embryos, and Fam46a knockdown induces abnormalities in the eye formation and the body color. At the neurula stage, Fam46a upregulates the expression of PPE genes and inhibits neural crest formation. We also show that Fam46a physically interacts with Smad1/Smad4 and positively regulates BMP signaling. From these results, we conclude that Fam46a is required for PPE formation via the positive regulation of BMP signaling. Our study provides a new mechanism of ectodermal patterning via cell-autonomous regulation of BMP signaling in the PPE.

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The Role of Smad Proteins for Development, Differentiation and Dedifferentiation of Neurons

Cited by 10 publications

References 241 publications

A Smad3 transgenic reporter reveals TGF-beta control of zebrafish spinal cord development

A Smad3 transgenic reporter reveals TGF-beta control of zebrafish spinal cord development

An update on human astrocytes and their role in development and disease

Fam46a regulates BMP-dependent pre-placodal ectoderm differentiation in Xenopus

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