HLH-2/E2A Expression Links Stochastic and Deterministic Elements of a Cell Fate Decision during C. elegans Gonadogenesis

Attner, Michelle Andrea; Keil, Wolfgang W.; Benavidez, Justin M.; Greenwald, Iva

doi:10.1016/j.cub.2019.07.062

Cited by 26 publications

(29 citation statements)

References 45 publications

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“…2A). As reported recently (Attner et al, 2019), GFP::hlh-2 turns on at the second 198 division of Z1/Z4 cells in Z1.pp and Z4.aa. We also detected onset of nhr-67::GFP in 199 these cells in some animals, though it appears that their expression is weaker in 200 Z1.pp/Z4.aa as compared to GFP::hlh-2, but becomes robust in the AC/VU cells prior to 201 specification.…”

supporting

confidence: 73%

“…During the mid-L3 stage, a al., 2018;Verghese et al, 2011). Interestingly, three of these TFs (egl-43, hlh-2 and 93 nhr-67) also play key roles in the specification of the AC and VU cell fates during the L2 94 stage (Attner et al, 2019;Hwang et al, 2007;Karp and Greenwald, 2004;Sallee et al, 95 2017;Verghese et al, 2011). How these four TFs function, independently and together, 96 to regulate both specification and invasive activity of the differentiated AC is poorly 97 understood.…”

mentioning

confidence: 99%

“…S1A) (Sturm et al, 2018). As three of four pro-invasive TFs (egl-43, 128 hlh-2 and nhr-67) also function during AC specification (Attner et al, 2019;Hwang et al, 129 2007;Karp and Greenwald, 2004;Sallee et al, 2017;Verghese et al, 2011), we 130 assessed TF depletions in a genetic background where only the AC and neighboring 131 uterine cells are sensitive to RNAi following the AC/VU decision (Matus et al, 2010). 132…”

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A developmental gene regulatory network for invasive differentiation of theC. elegansanchor cell

Medwig-Kinney

Smith

Palmisano

et al. 2019

Preprint

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STATEMENT 24 Basement membrane invasion by the C. elegans anchor cell is coordinated by a 25 dynamic gene regulatory network encompassing cell cycle dependent and independent 26 sub-circuits. 27 28 ABSTRACT 29 Cellular invasion is a key part of development, immunity, and disease. Using the in vivo 30 model of C. elegans anchor cell invasion, we characterize the gene regulatory network 31 that promotes invasive differentiation. The anchor cell is initially specified in a stochastic 32 cell fate decision mediated by Notch signaling. Previous research has identified four 33 conserved transcription factors, fos-1a (Fos), egl-43 (EVI1/MEL), hlh-2 (E/Daughterless) 34and nhr-67 (NR2E1/TLX), that mediate anchor cell specification and/or invasive 35 differentiation. Connections between these transcription factors and the underlying cell 36 biology that they regulate is poorly understood. Here, using genome editing and RNA 37 interference, we examine transcription factor interactions prior to and after anchor cell 38 specification. During invasion we identify that egl-43, hlh-2, and nhr-67 function together 39 in a type I coherent feed-forward loop with positive feedback. Conversely, prior to 40 specification, these transcription factors function independent of one another to regulate 41 LIN-12 (Notch) activity. Together, these results demonstrate that, although the same 42 transcription factors can function in fate specification and differentiated cell behavior, a 43 gene regulatory network can be rapidly re-wired to reinforce a post-mitotic, pro-invasive 44 state. 45 46 Medwig-Kinney, et al. (2019) GRN for invasive differentiation 3

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confidence: 99%

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A developmental gene regulatory network for invasive differentiation of theC. elegansanchor cell

Medwig-Kinney

Smith

Palmisano

et al. 2019

Preprint

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“…The AC is specified during the second larval stage (L2) of C. elegans development, when two equivalent precursor cells (Z1.ppp and Z4.aaa) adopt either the AC or the ventral uterine (VU) fate, depending on stochastic differences in LAG-2 Delta/ LIN-12 Notch signaling [4,5]. This initially small difference is amplified by two extra stochastic events, the division order of Z1 and Z4 and the expression onset of hlh-2 in Z1.pp and Z1.aa [6]. The cell that exhibits higher lag-2 expression levels adopts the "default" AC fate and activates LIN-12 Notch signaling in the adjacent cell to induce the VU fate [7].…”

Section: Introductionmentioning

confidence: 99%

The Caenorhabditis elegans homolog of the Evi1 proto-oncogene, egl-43, coordinates G1 cell cycle arrest with pro-invasive gene expression during anchor cell invasion

et al. 2020

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Cell invasion allows cells to migrate across compartment boundaries formed by basement membranes. Aberrant cell invasion is a first step during the formation of metastases by malignant cancer cells. Anchor cell (AC) invasion in C. elegans is an excellent in vivo model to study the regulation of cell invasion during development. Here, we have examined the function of egl-43, the homolog of the human Evi1 proto-oncogene (also called MECOM), in the invading AC. egl-43 plays a dual role in this process, firstly by imposing a G1 cell cycle arrest to prevent AC proliferation, and secondly, by activating pro-invasive gene expression. We have identified the AP-1 transcription factor fos-1 and the Notch homolog lin-12 as critical egl-43 targets. A positive feedback loop between fos-1 and egl-43 induces pro-invasive gene expression in the AC, while repression of lin-12 Notch expression by egl-43 ensures the G1 cell cycle arrest necessary for invasion. Reducing lin-12 levels in egl-43 depleted animals restored the G1 arrest, while hyperactivation of lin-12 signaling in the differentiated AC was sufficient to induce proliferation. Taken together, our data have identified egl-43 Evi1 as an important factor coordinating cell invasion with cell cycle arrest.

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“…A positive feedback loop established by upregulation of the Notch ligand LAG-2 (DSL) in the future AC and by lateral inhibition via activation of the Notch receptor LIN-12 (Notch) in the adjacent VU precursor underly the AC/VU decision (Seydoux and Greenwald, 1989 ; Greenwald and Kovall, 2013 ). hlh-2 ( TCF3, TCF4,TCF12 ) encodes a basic helix-loop-helix transcription factor that up-regulates lin-12 expression in the presumptive VU cell (Attner et al, 2019 ). The initial imbalance in Notch signaling is driven by the onset of hlh-2 expression, which is linked to the relative birth order of the AC/VU ancestor cells Z1.ppp and Z4.aaa.…”

Section: Introductionmentioning

confidence: 99%

To Divide or Invade: A Look Behind the Scenes of the Proliferation-Invasion Interplay in the Caenorhabditis elegans Anchor Cell

Lattmann

Deng

Hajnal

2021

Front. Cell Dev. Biol.

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Cell invasion is defined by the capability of cells to migrate across compartment boundaries established by basement membranes (BMs). The development of complex organs involves regulated cell growth and regrouping of different cell types, which are enabled by controlled cell proliferation and cell invasion. Moreover, when a malignant tumor takes control over the body, cancer cells evolve to become invasive, allowing them to spread to distant sites and form metastases. At the core of the switch between proliferation and invasion are changes in cellular morphology driven by remodeling of the cytoskeleton. Proliferative cells utilize their actomyosin network to assemble a contractile ring during cytokinesis, while invasive cells form actin-rich protrusions, called invadopodia that allow them to breach the BMs. Studies of developmental cell invasion as well as of malignant tumors revealed that cell invasion and proliferation are two mutually exclusive states. In particular, anchor cell (AC) invasion during Caenorhabditis elegans larval development is an excellent model to study the transition from cell proliferation to cell invasion under physiological conditions. This mini-review discusses recent insights from the C. elegans AC invasion model into how G1 cell-cycle arrest is coordinated with the activation of the signaling networks required for BM breaching. Many regulators of the proliferation-invasion network are conserved between C. elegans and mammals. Therefore, the worm may provide important clues to better understand cell invasion and metastasis formation in humans.

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HLH-2/E2A Expression Links Stochastic and Deterministic Elements of a Cell Fate Decision during C. elegans Gonadogenesis

Cited by 26 publications

References 45 publications

A developmental gene regulatory network for invasive differentiation of theC. elegansanchor cell

A developmental gene regulatory network for invasive differentiation of theC. elegansanchor cell

The Caenorhabditis elegans homolog of the Evi1 proto-oncogene, egl-43, coordinates G1 cell cycle arrest with pro-invasive gene expression during anchor cell invasion

To Divide or Invade: A Look Behind the Scenes of the Proliferation-Invasion Interplay in the Caenorhabditis elegans Anchor Cell

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