Reconstruction of rat retinal progenitor cell lineages in vitro reveals a surprising degree of stochasticity in cell fate decisions

ABSTRACT The intracellular signaling controlling neural stem/progenitor cell (NSC) self-renewal and neuronal/glial differentiation is not fully understood. We show here that Shp2, an introcellular tyrosine phosphatase with two SH2 domains, plays a critical role in NSC activities. Conditional deletion of Shp2 in neural progenitor cells mediated by Nestin-Cre resulted in early postnatal lethality, impaired corticogenesis, and reduced proliferation of progenitor cells in the ventricular zone. In vitro analyses suggest that Shp2 mediates basic fibroblast growth factor signals in stimulating self-renewing proliferation of NSCs, partly through control of Bmi-1 expression. Furthermore, Shp2 regulates cell fate decisions, by promoting neurogenesis while suppressing astrogliogenesis, through reciprocal regulation of the Erk and Stat3 signaling pathways. Together, these results identify Shp2 as a critical signaling molecule in coordinated regulation of progenitor cell proliferation and neuronal/astroglial cell differentiation.

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Stabilization of β-catenin promotes melanocyte specification at the expense of the Schwann cell lineage

Development ◽

10.1242/dev.194407 ◽

2021 ◽

Author(s):

Sophie Colombo ◽

Valérie Petit ◽

Roselyne Y. Wagner ◽

Delphine Champeval ◽

Ichiro Yajima ◽

...

Keyword(s):

Schwann Cell ◽

Cell Fate ◽

Active Form ◽

Cell Lineage ◽

Temporal Window ◽

Cell Fate Decisions ◽

Cell Lineages ◽

Canonical Wnt ◽

Second Wave

The canonical Wnt/β-catenin pathway governs a multitude of developmental processes in various cell lineages, including the melanocyte lineage. Indeed, β-catenin regulates Mitf-M transcription, the master regulator of this lineage. The first wave of melanocytes to colonize the skin is directly derived from neural crest cells, while the second wave of melanocytes is derived from Schwann-cell precursors (SCPs). We investigated the influence of β-catenin in the development of melanocytes of the first and second waves by generating mice expressing a constitutively active form of β-catenin in cells expressing tyrosinase. Constitutive activation of β-catenin did not affect the development of truncal melanoblasts but led to marked hyperpigmentation of the paws. By activating β-catenin at various stages of development (E8.5-E11.5), we showed that the activation of β-catenin in bipotent SCPs favored melanoblast specification at the expense of Schwann cells in the limbs within a specific temporal window. Furthermore, in vitro hyperactivation of the Wnt/β-catenin pathway, which is required for melanocyte development, induces activation of Mitf-M, in turn repressing FoxD3 expression. In conclusion, β-catenin overexpression promotes SCP cell fate decisions towards the melanocyte lineage.

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Phosphorylation state of the histone variant H2A.X controls human stem and progenitor cell fate decisions

Cell Reports ◽

10.1016/j.celrep.2021.108818 ◽

2021 ◽

Vol 34 (10) ◽

pp. 108818

Author(s):

Luca Orlando ◽

Borko Tanasijevic ◽

Mio Nakanishi ◽

Jennifer C. Reid ◽

Juan L. García-Rodríguez ◽

...

Keyword(s):

Cell Fate ◽

Progenitor Cell ◽

Histone Variant ◽

Phosphorylation State ◽

Cell Fate Decisions

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Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2.

Molecular and Cellular Biology ◽

10.1128/mcb.16.3.952 ◽

1996 ◽

Vol 16 (3) ◽

pp. 952-959 ◽

Cited By ~ 323

Author(s):

J J Hsieh ◽

T Henkel ◽

P Salmon ◽

E Robey ◽

M G Peterson ◽

...

Keyword(s):

Amino Acid ◽

Cell Fate ◽

Transcriptional Repression ◽

Epstein Barr Virus ◽

Cell Fate Decisions ◽

Barr Virus ◽

Amino Acid Region ◽

Nuclear Events ◽

Epstein Barr

The Notch/Lin-12/Glp-1 receptor family participates in cell-cell signaling events that influence cell fate decisions. Although several Notch homologs and receptor ligands have been identified, the nuclear events involved in this pathway remain incompletely understood. A truncated form of Notch, consisting only of the intracellular domain (NotchIC), localizes to the nucleus and functions as an activated receptor. Using both an in vitro binding assay and a cotransfection assay based on the two-hybrid principle, we show that mammalian NotchIC interacts with the transcriptional repressor CBF1, which is the human homolog of Drosophila Suppressor of Hairless. Cotransfection assays using segments of mouse NotchIC and CBF1 demonstrated that the N-terminal 114-amino-acid region of mouse NotchIC contains the CBF1 interactive domain and that the cdc10/ankyrin repeats are not essential for this interaction. This result was confirmed in immunoprecipation assays in which the N-terminal 114-amino-acid segment of NotchIC, but not the ankyrin repeat region, coprecipitated with CBF1. Mouse NotchIC itself is targeted to the transcriptional repression domain (aa179 to 361) of CBF1. Furthermore, transfection assays in which mouse NotchIC was targeted through Gal4-CBF1 or through endogenous cellular CBF1 indicated that NotchIC transactivates gene expression via CBF1 tethering to DNA. Transactivation by NotchIC occurs partially through abolition of CBF1-mediated repession. This same mechanism is used by Epstein-Barr virus EBNA2. Thus, mimicry of Notch signal transduction is involved in Epstein-Barr virus-driven immortalization.

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SyNPL: Synthetic Notch pluripotent cell lines to monitor and manipulate cell interactions in vitro and in vivo

10.1101/2021.09.24.461672 ◽

2021 ◽

Author(s):

Mattias Malaguti ◽

Rosa Portero Migueles ◽

Jennifer Annoh ◽

Daina Sadurska ◽

Guillaume Blin ◽

...

Keyword(s):

Cell Fate ◽

Cell Lines ◽

Modular Design ◽

Cell Interactions ◽

Cell Populations ◽

Cell Contact ◽

Pluripotent Cells ◽

Cell Fate Decisions ◽

Cell Cell

ABSTRACTCell-cell interactions govern differentiation and cell competition in pluripotent cells during early development, but the investigation of such processes is hindered by a lack of efficient analysis tools. Here we introduce SyNPL: clonal pluripotent stem cell lines which employ optimised Synthetic Notch (SynNotch) technology to report cell-cell interactions between engineered “sender” and “receiver” cells in cultured pluripotent cells and chimaeric mouse embryos. A modular design makes it straightforward to adapt the system for programming differentiation decisions non-cell-autonomously in receiver cells in response to direct contact with sender cells. We demonstrate the utility of this system by enforcing neuronal differentiation at the boundary between two cell populations. In summary, we provide a new tool which could be used to identify cell interactions and to profile changes in gene or protein expression that result from direct cell-cell contact with defined cell populations in culture and in early embryos, and which can be adapted to generate synthetic patterning of cell fate decisions.

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