Smad2 and Smad3 cooperate and antagonize simultaneously in vertebrate neurogenesis

Míguez, David G.; Gil-Guiñón, Estel; Pons, Sebastián; Martı́, Elisa

doi:10.1242/jcs.130435

Cited by 27 publications

(33 citation statements)

References 44 publications

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“…Compatible with previous findings, Smad2 was not detected (Garcia-Campmany and Marti, 2007). Reports differ as to the extent of Smad2 expression in the neural tube during embryogenesis (Garcia-Campmany and Marti, 2007;Miguez et al, 2013).…”

Section: B) No Immunoreactivity Was Detected In Smad3supporting

confidence: 65%

Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination

et al. 2014

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In the embryonic CNS, development of myelin-forming oligodendrocytes is limited by bone morphogenetic proteins, which constitute one arm of the transforming growth factor-β (Tgfβ) family and signal canonically via Smads 1/5/8. Tgfβ ligands and Activins comprise the other arm and signal via Smads 2/3, but their roles in oligodendrocyte development are incompletely characterized. Here, we report that Tgfβ ligands and activin B (ActB) act in concert in the mammalian spinal cord to promote oligodendrocyte generation and myelination. In mouse neural tube, newly specified oligodendrocyte progenitors (OLPs) are first exposed to Tgfβ ligands in isolation, then later in combination with ActB during maturation. In primary OLP cultures, Tgfβ1 and ActB differentially activate canonical Smad3 and non-canonical MAP kinase signaling. Both ligands enhance viability, and Tgfβ1 promotes proliferation while ActB supports maturation. Importantly, co-treatment strongly activates both signaling pathways, producing an additive effect on viability and enhancing both proliferation and differentiation such that mature oligodendrocyte numbers are substantially increased. Co-treatment promotes myelination in OLPneuron co-cultures, and maturing oligodendrocytes in spinal cord white matter display strong Smad3 and MAP kinase activation. In spinal cords of ActB-deficient Inhbb −/− embryos, apoptosis in the oligodendrocyte lineage is increased and OLP numbers transiently reduced, but numbers, maturation and myelination recover during the first postnatal week. Smad3 −/− mice display a more severe phenotype, including diminished viability and proliferation, persistently reduced mature and immature cell numbers, and delayed myelination. Collectively, these findings suggest that, in mammalian spinal cord, Tgfβ ligands and ActB together support oligodendrocyte development and myelin formation.

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Section: B) No Immunoreactivity Was Detected In Smad3supporting

confidence: 65%

Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination

et al. 2014

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“…2A and S3). In contrast to what is seen for SMAD2 and 3 in the chicken neural tube (Lan, 2011) (Miguez et al, 2013), only high doses of Fig. 7.…”

Section: Discussionmentioning

confidence: 63%

“…smad2 morpholino give an appreciable reduction of 12xSBE-depending reporter expression (Table 4). However, the different techniques used to inhibit and study Smad2 in zebrafish (this work) and chicken (Miguez et al, 2013) (i.e., morpholino vs. shorthairpin RNA; microinjection of eggs vs. electroporation of neural tube; stable line vs. transient expression) can explain the differences. Alternatively, Smad2-3a-3b and 4 interact in different ways in neural tube formation of the two animals.…”

Section: Discussionmentioning

confidence: 93%

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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“…We next assessed the endogenous activity of the TGF-/BMP pathways in vivo by electroporating a BMP (BRE:eGFP: Le Dreau et al, 2014; or a TGF- responsive (CAGA12-GFP; (Miguez et al, 2013) fluorescent reporter construct, together with a control H2B-RFP vector (Fig. 1H).…”

Section: Smad3 Activitymentioning

confidence: 99%

Cell intercalation driven by SMAD3 underlies secondary neural tube formation

Gonzalez-Gobartt

Blanco-Ameijeiras

Usieto

et al. 2020

Preprint

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Body axis elongation is a hallmark of the vertebrate embryo, involving the architectural remodelling of the tailbud. Although it is clear how bi-potential neuro-mesodermal progenitors (NMPs) contribute to embryo elongation, the dynamic events that lead to de novo lumen formation and that culminate in the formation of a 3-Dimensional, secondary neural tube from NMPs, are poorly understood. Here, we used in vivo imaging of the chicken embryo to show that cell intercalation downstream of TGF-beta/SMAD3 signalling is required for secondary neural tube formation. Our analysis describes the initial events in embryo elongation including lineage restriction, the epithelial-to-mesenchymal transition of NMPs, and the initiation of lumen formation. Importantly, we show that the resolution of a single, centrally positioned continuous lumen, which occurs through the intercalation of central cells, requires SMAD3 activity. We anticipate that these findings will be relevant to understand caudal, skin-covered neural tube defects, amongst the most frequent birth defects detected in humans.

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Smad2 and Smad3 cooperate and antagonize simultaneously in vertebrate neurogenesis

Cited by 27 publications

References 44 publications

Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination

Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination

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

Cell intercalation driven by SMAD3 underlies secondary neural tube formation

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