Stem cells living with a Notch

Koch, Ute; Lehal, Rajwinder; Radtke, Freddy

doi:10.1242/dev.080614

Cited by 255 publications

(227 citation statements)

References 157 publications

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“…Notch1 effectively inhibits differentiation in many cellular systems, thereby preserving stemness (62). In agreement with that fact, N1ICD maintained expression of genes associated with undifferentiated vCTBs and CCTs, E-cadherin and HAI-1, and suppressed STB formation of fusogenic precursors as well as differentiation-dependent induction of CGβ.…”

Section: Discussionsupporting

confidence: 64%

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Notch1 controls development of the extravillous trophoblast lineage in the human placenta

Haider

Meinhardt

Saleh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

124

144

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Development of the human placenta and its different epithelial trophoblasts is crucial for a successful pregnancy. Besides fusing into a multinuclear syncytium, the exchange surface between mother and fetus, progenitors develop into extravillous trophoblasts invading the maternal uterus and its spiral arteries. Migration into these vessels promotes remodelling and, as a consequence, adaption of blood flow to the fetal–placental unit. Defects in remodelling and trophoblast differentiation are associated with severe gestational diseases, such as preeclampsia. However, mechanisms controlling human trophoblast development are largely unknown. Herein, we show that Notch1 is one such critical regulator, programming primary trophoblasts into progenitors of the invasive differentiation pathway. At the 12th wk of gestation, Notch1 is exclusively detected in precursors of the extravillous trophoblast lineage, forming cell columns anchored to the uterine stroma. At the 6th wk, Notch1 is additionally expressed in clusters of villous trophoblasts underlying the syncytium, suggesting that the receptor initiates the invasive differentiation program in distal regions of the developing placental epithelium. Manipulation of Notch1 in primary trophoblast models demonstrated that the receptor promotes proliferation and survival of extravillous trophoblast progenitors. Notch1 intracellular domain induced genes associated with stemness of cell columns, myc and VE-cadherin, in Notch1−fusogenic precursors, and bound to themycpromoter and enhancer region at RBPJκ cognate sequences. In contrast, Notch1 repressed syncytialization and expression of TEAD4 and p63, two regulators controlling self-renewal of villous cytotrophoblasts. Our results revealed Notch1 as a key factor promoting development of progenitors of the extravillous trophoblast lineage in the human placenta.

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Section: Discussionsupporting

confidence: 64%

“…Notch signaling in stem cells is highly complex and exerts different effects in tissues and organs (23,62). Accordingly, Notch was shown to promote or inhibit self-renewal, differentiation, and survival, depending on the specific cellular context.…”

Section: Discussionmentioning

confidence: 99%

Notch1 controls development of the extravillous trophoblast lineage in the human placenta

Haider

Meinhardt

Saleh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

124

144

View full text Add to dashboard Cite

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“…In addition to C. elegans GSCs, other types of stem cells also depend on Notch signaling for self-renewal (see Introduction) (reviewed in ref. 8). Critical downstream targets have also been identified, the most well-studied being genes encoding the Hes/Hey family of bHLH transcription factors.…”

Section: Discussionmentioning

confidence: 99%

“…Although Notch signaling regulates stem cells in vertebrates, including those in the mammalian muscle, brain, and intestine (reviewed in ref. 8), its use in the nematode C. elegans to maintain GSCs provides the best defined and most tractable paradigm (Fig. 1A).…”

mentioning

confidence: 99%

Discovery of two GLP-1/Notch target genes that account for the role of GLP-1/Notch signaling in stem cell maintenance

Kershner

Shin

Hansen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

102

241

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A stem cell’s immediate microenvironment creates an essential “niche” to maintain stem cell self-renewal. Many niches and their intercellular signaling pathways are known, but for the most part, the key downstream targets of niche signaling remain elusive. Here, we report the discovery of two GLP-1/Notch target genes, lst-1 (lateral signaling target) and sygl-1 (synthetic Glp), that function redundantly to maintain germ-line stem cells (GSCs) in the nematode Caenorhabditis elegans. Whereas lst-1 and sygl-1 single mutants appear normal, lst-1 sygl-1 double mutants are phenotypically indistinguishable from glp-1/Notch mutants. Multiple lines of evidence demonstrate that GLP-1/Notch signaling activates lst-1 and sygl-1 expression in GSCs within the niche. Therefore, these two genes fully account for the role of GLP-1/Notch signaling in GSC maintenance. Importantly, lst-1 and sygl-1 are not required for GLP-1/Notch signaling per se. We conclude that lst-1 and sygl-1 forge a critical link between Notch signaling and GSC maintenance.

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“…The evolutionarily conserved NOTCH signalling pathway is a key regulator of cell specification during embryonic development and adult tissue homeostasis (reviewed by Andersson et al, 2011;Artavanis-Tsakonas and Muskavitch, 2010;Guruharsha et al, 2012;Koch et al, 2013). In mammalian cells, there are four NOTCH receptors (NOTCH1-4) and several transmembrane ligands such as Delta-like (DLL1, DLL3, DLL4) and Jagged (JAG1 and JAG2).…”

Section: Introductionmentioning

confidence: 99%

NOTCH activation interferes with cell fate specification in the gastrulating mouse embryo

et al. 2015

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NOTCH signalling is an evolutionarily conserved pathway involved in intercellular communication essential for cell fate choices during development. Although dispensable for early aspects of mouse development, canonical RBPJ-dependent NOTCH signalling has been shown to influence lineage commitment during embryonic stem cell (ESC) differentiation. NOTCH activation in ESCs promotes the acquisition of a neural fate, whereas its suppression favours their differentiation into cardiomyocytes. This suggests that NOTCH signalling is implicated in the acquisition of distinct embryonic fates at early stages of mammalian development. In order to investigate in vivo such a role for NOTCH signalling in shaping cell fate specification, we use genetic approaches to constitutively activate the NOTCH pathway in the mouse embryo. Early embryonic development, including the establishment of anterior-posterior polarity, is not perturbed by forced NOTCH activation. By contrast, widespread NOTCH activity in the epiblast triggers dramatic gastrulation defects. These are fully rescued in a RBPJ-deficient background. Epiblast-specific NOTCH activation induces acquisition of neurectoderm identity and disrupts the formation of specific mesodermal precursors including the derivatives of the anterior primitive streak, the mouse organiser. In addition, we show that forced NOTCH activation results in misregulation of NODAL signalling, a major determinant of early embryonic patterning. Our study reveals a previously unidentified role for canonical NOTCH signalling during mammalian gastrulation. It also exemplifies how in vivo studies can shed light on the mechanisms underlying cell fate specification during in vitro directed differentiation.

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Stem cells living with a Notch

Cited by 255 publications

References 157 publications

Notch1 controls development of the extravillous trophoblast lineage in the human placenta

Notch1 controls development of the extravillous trophoblast lineage in the human placenta

Discovery of two GLP-1/Notch target genes that account for the role of GLP-1/Notch signaling in stem cell maintenance

NOTCH activation interferes with cell fate specification in the gastrulating mouse embryo

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