CtBP impedes JNK- and Upd/STAT-driven cell fate misspecifications in regenerating Drosophila imaginal discs

Regeneration following tissue damage often necessitates a mechanism for cellular re-programming, so that surviving cells can give rise to all cell types originally found in the damaged tissue. This process, if unchecked, can also generate cell types that are inappropriate for a given location. We conducted a screen for genes that negatively regulate the frequency of notum-to-wing transformations following genetic ablation and regeneration of the wing pouch, from which we identified mutations in the transcriptional co-repressor C-terminal Binding Protein (CtBP). When CtBP function is reduced, ablation of the pouch can activate the JNK/AP-1 and JAK/STAT pathways in the notum to destabilize cell fates. Ectopic expression of Wingless and Dilp8 precede the formation of the ectopic pouch, which is subsequently generated by recruitment of both anterior and posterior cells near the compartment boundary. Thus, CtBP stabilizes cell fates following damage by opposing the destabilizing effects of the JNK/AP-1 and JAK/STAT pathways.

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Maintenance of Cell Fates by Regulation of the Histone Variant H3.3 in Caenorhabditis elegans

10.1101/294827 ◽

2018 ◽

Author(s):

Yukimasa Shibata ◽

Kiyoji Nishiwaki

Keyword(s):

Caenorhabditis Elegans ◽

Cell Fate ◽

Binding Protein ◽

Ectopic Expression ◽

Cell Types ◽

Histone Variants ◽

Histone Variant ◽

Histone H4 ◽

Cell Fates ◽

Selector Genes

HighlightsTLK-1 maintains cell fates by repression of selector genesTLK-1 and downstream H3 chaperone CAF1 inhibit H3.3 depositionLoss of sin-3 suppresses the defect in cell-fate maintenance of tlk-1 mutantsAcH4-binding protein BET-1 is necessary for sin-3 suppressionSummaryCell-fate maintenance is important to preserve the variety of cell types that are essential for the formation and function of tissues. We previously showed that the acetylated histone H4-binding protein BET-1 maintains cell fate by recruiting the histone variant H2A.z. Here, we report that Caenorhabditis elegans tousled-like kinase TLK-1 and the histone H3 chaperone CAF1 maintain cell fate by preventing the incorporation of histone variant H3.3 into nucleosomes, thereby repressing ectopic expression of transcription factors that induce cell-fate specification. Genetic analyses suggested that TLK-1 and BET-1 act in parallel pathways. In tlk-1 mutants, the loss of SIN-3, which promotes histone acetylation, suppressed a defect in cell-fate maintenance in a manner dependent on MYST family histone acetyltransferase MYS-2 and BET-1. sin-3 mutation also suppressed abnormal H3.3 incorporation. Thus, we propose that the regulation and interaction of histone variants play crucial roles in cell-fate maintenance through the regulation of selector genes.

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Patterning of Drosophila leg sensory organs through combinatorial signaling by hedgehog, decapentaplegic and wingless

Development ◽

10.1242/dev.126.13.2891 ◽

1999 ◽

Vol 126 (13) ◽

pp. 2891-2899 ◽

Cited By ~ 1

Author(s):

R. Hays ◽

K.T. Buchanan ◽

C. Neff ◽

T.V. Orenic

Keyword(s):

Cell Fate ◽

Imaginal Disc ◽

Sensory Cell ◽

Individual Cell ◽

Cell Types ◽

Cell Fates ◽

Cubitus Interruptus ◽

Compartment Boundary ◽

Local Environments ◽

Ectopic Activation

During development, global patterning events initiate signal transduction cascades which gradually establish an array of individual cell fates. Many of the genes which pattern Drosophila are expressed throughout development and specify diverse cell types by creating unique local environments which establish the expression of locally acting genes. This process is exemplified by the patterning of leg microchaete rows. hairy (h) is expressed in a spatially restricted manner in the leg imaginal disc and functions to position adult leg bristle rows by negatively regulating the proneural gene achaete, which specifies sensory cell fates. While much is known about the events that partition the leg imaginal disc and about sensory cell differentiation, the mechanisms that refine early patterning events to the level of individual cell fate specification are not well understood. We have investigated the regulation of h expression along the dorsal/ventral (D/V) axis of the leg adjacent to the anterior/posterior (A/P) compartment boundary and have found that it requires input from both D/V and A/P patterning mechanisms. Expression of the D/V axis h stripe (D/V-h) is controlled by dorsal- and ventral-specific enhancer elements which are targets of Decapentaplegic (Dpp) and Wingless (Wg) signaling, respectively, but which are also dependent on Hedgehog (Hh) signaling for activation. D/V-h expression is lost in smoothened mutant clones and is specifically activated by exogenously supplied Cubitus interruptus (Ci). D/V-h expression is also lost in clones deficient for Dpp and Wg signaling, but ectopic activation of D/V-h by Dpp and Wg is limited to the A/P compartment boundary where endogenous levels of full-length Ci are high. We propose that D/V-h expression is regulated in a non-linear pathway in which Ci plays a dual role. In addition to serving as an upstream activator of Dpp and Wg, Ci acts combinatorially with them to activate D/V-h expression.

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C. elegans LIN-28 controls temporal cell-fate progression by regulating LIN-46 expression via the 5’UTR of lin-46 mRNA

10.1101/697490 ◽

2019 ◽

Cited By ~ 2

Author(s):

Orkan Ilbay ◽

Charles Nelson ◽

Victor Ambros

Keyword(s):

Cell Fate ◽

Cellular Differentiation ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Cell Types ◽

Cell Fates ◽

C Elegans ◽

L1 And L2 ◽

Proliferative Cell

ABSTRACTHuman Lin28 is a conserved RNA-binding protein that promotes proliferation and pluripotency and can be oncogenic. Lin28 and C. elegans LIN-28 bind to precursor RNAs of the conserved, cellular differentiation-promoting, microRNA let-7 and inhibits production of mature let-7 microRNA. Lin28/LIN-28 also binds to and regulates many mRNAs in various cell types. However, the determinants and consequences of these LIN-28-mRNA interactions are not well understood. Here, we report that LIN-28 in C. elegans represses the expression of LIN-46, a downstream protein in the heterochronic pathway, via the 5’ UTR of the lin-46 mRNA. We show that both LIN-28 and the 5’UTR of lin-46 are required to prevent LIN-46 expression in the L1 and L2 stages, and that precocious LIN-46 expression is sufficient to skip L2 stage proliferative cell-fates, resulting in heterochronic defects similar to the ones observed in lin-28(0) animals. We propose that the lin-46 5’UTR mediates LIN-28 binding to and repression of the lin-46 mRNA. Our results demonstrate that precocious LIN-46 expression alone can account for lin-28(0) phenotypes, demonstrating the biological importance of regulation of individual target mRNAs by LIN-28.

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Histone Acetyltransferases and Stem Cell Identity

Cancers ◽

10.3390/cancers13102407 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2407

Author(s):

Ruicen He ◽

Arthur Dantas ◽

Karl Riabowol

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Fate ◽

Epigenetic Modification ◽

Cell Types ◽

Histone Acetyltransferases ◽

Specific Cell ◽

Cell Fates ◽

Cell Identity ◽

Hematopoietic Stem

Acetylation of histones is a key epigenetic modification involved in transcriptional regulation. The addition of acetyl groups to histone tails generally reduces histone-DNA interactions in the nucleosome leading to increased accessibility for transcription factors and core transcriptional machinery to bind their target sequences. There are approximately 30 histone acetyltransferases and their corresponding complexes, each of which affect the expression of a subset of genes. Because cell identity is determined by gene expression profile, it is unsurprising that the HATs responsible for inducing expression of these genes play a crucial role in determining cell fate. Here, we explore the role of HATs in the maintenance and differentiation of various stem cell types. Several HAT complexes have been characterized to play an important role in activating genes that allow stem cells to self-renew. Knockdown or loss of their activity leads to reduced expression and or differentiation while particular HATs drive differentiation towards specific cell fates. In this study we review functions of the HAT complexes active in pluripotent stem cells, hematopoietic stem cells, muscle satellite cells, mesenchymal stem cells, neural stem cells, and cancer stem cells.

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Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis

Development ◽

10.1242/dev.127.17.3865 ◽

2000 ◽

Vol 127 (17) ◽

pp. 3865-3876

Author(s):

M.S. Rones ◽

K.A. McLaughlin ◽

M. Raffin ◽

M. Mercola

Keyword(s):

Gene Expression ◽

Notch Signaling ◽

Cell Fate ◽

Notch Pathway ◽

Cell Types ◽

Myocardial Cell ◽

Dominant Negative ◽

Cell Fates ◽

Cell Fate Decisions ◽

Heart Field

Notch signaling mediates numerous developmental cell fate decisions in organisms ranging from flies to humans, resulting in the generation of multiple cell types from equipotential precursors. In this paper, we present evidence that activation of Notch by its ligand Serrate apportions myogenic and non-myogenic cell fates within the early Xenopus heart field. The crescent-shaped field of heart mesoderm is specified initially as cardiomyogenic. While the ventral region of the field forms the myocardial tube, the dorsolateral portions lose myogenic potency and form the dorsal mesocardium and pericardial roof (Raffin, M., Leong, L. M., Rones, M. S., Sparrow, D., Mohun, T. and Mercola, M. (2000) Dev. Biol., 218, 326–340). The local interactions that establish or maintain the distinct myocardial and non-myocardial domains have never been described. Here we show that Xenopus Notch1 (Xotch) and Serrate1 are expressed in overlapping patterns in the early heart field. Conditional activation or inhibition of the Notch pathway with inducible dominant negative or active forms of the RBP-J/Suppressor of Hairless [Su(H)] transcription factor indicated that activation of Notch feeds back on Serrate1 gene expression to localize transcripts more dorsolaterally than those of Notch1, with overlap in the region of the developing mesocardium. Moreover, Notch pathway activation decreased myocardial gene expression and increased expression of a marker of the mesocardium and pericardial roof, whereas inhibition of Notch signaling had the opposite effect. Activation or inhibition of Notch also regulated contribution of individual cells to the myocardium. Importantly, expression of Nkx2. 5 and Gata4 remained largely unaffected, indicating that Notch signaling functions downstream of heart field specification. We conclude that Notch signaling through Su(H) suppresses cardiomyogenesis and that this activity is essential for the correct specification of myocardial and non-myocardial cell fates.

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Hypoxia-Inducible Factors 1α and 2α Regulate Trophoblast Differentiation

Molecular and Cellular Biology ◽

10.1128/mcb.25.23.10479-10491.2005 ◽

2005 ◽

Vol 25 (23) ◽

pp. 10479-10491 ◽

Cited By ~ 132

Author(s):

Karen D. Cowden Dahl ◽

Benjamin H. Fryer ◽

Fiona A. Mack ◽

Veerle Compernolle ◽

Emin Maltepe ◽

...

Keyword(s):

Cell Fate ◽

Cell Types ◽

Hypoxia Inducible Factors ◽

Low Oxygen ◽

Placental Development ◽

Cell Fates ◽

Trophoblast Stem Cells ◽

Cell Fate Decisions ◽

Hypoxic Environment ◽

Life Threatening

ABSTRACT Placental development initially occurs in a low-oxygen (O2) or hypoxic environment. In this report we show that two hypoxia-inducible factors (HIFs), HIF1α and HIF2α, are essential for determining murine placental cell fates. HIF is a heterodimer composed of HIFα and HIFβ (ARNT) subunits. Placentas from Arnt − / − and Hif1α − / − Hif2α −/− embryos exhibit defective placental vascularization and aberrant cell fate adoption. HIF regulation of Mash2 promotes spongiotrophoblast differentiation, a prerequisite for trophoblast giant cell differentiation. In the absence of Arnt or Hifα, trophoblast stem cells fail to generate these cell types and become labyrinthine trophoblasts instead. Therefore, HIF mediates placental morphogenesis, angiogenesis, and cell fate decisions, demonstrating that O2 tension is a critical regulator of trophoblast lineage determination. This novel genetic approach provides new insights into the role of O2 tension in the development of life-threatening pregnancy-related diseases such as preeclampsia.

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Control of cell fate and polarity in the adult abdominal segments of Drosophila by optomotor-blind

Development ◽

10.1242/dev.124.19.3715 ◽

1997 ◽

Vol 124 (19) ◽

pp. 3715-3726 ◽

Cited By ~ 10

Author(s):

A. Kopp ◽

I. Duncan

Keyword(s):

Cell Fate ◽

Anterior Part ◽

Ectopic Expression ◽

Mirror Image ◽

Posterior Compartment ◽

Anterior Portion ◽

Posterior Portion ◽

Anterior Compartment ◽

Compartment Boundary ◽

Hh Signaling

In an accompanying report (Kopp, A., Muskavitch, M. A. T. and Duncan, I. (1997) Development 124, 3703–3714), we show that Hh protein secreted by posterior compartment cells patterns the posterior portion of the anterior compartment in adult abdominal segments. Here we show that this function of hh is mediated by optomotor-blind (omb). omb- mutants mimic the effects of loss-of-function alleles of hh: structures from the posterior of the anterior compartment are lost, and often this region develops as a mirror image of the anterior portion. Structures from the anterior part of the posterior compartment are also lost. In the pupa, omb expression in abdominal histoblasts is highest at or near the compartment boundary, and decreases in a shallow gradient toward the anterior. This gradient is due to activation of omb by Hh secreted by posterior compartment cells. In contrast to imaginal discs, this Hh signaling is not mediated by dpp or wg. We describe several gain-of-function alleles that cause ectopic expression of omb in the anterior of the segment. Most of these cause the anterior region to develop with posterior characteristics without affecting polarity. However, an allele that drives high level ubiquitous expression of omb (QdFab) causes the anterior tergite to develop as a mirror-image duplication of the posterior tergite, a pattern opposite to that seen in omb- mutants. Ubiquitous expression of hh causes similar double-posterior patterning. We find that omb- alleles suppress this effect of ectopic hh expression and that posterior patterning becomes independent of hh in the QdFab mutant. These observations indicate that omb is the primary target of hh signaling in the adult abdomen. However, it is clear that other targets exist. One of these is likely Scruffy, a novel gene that we describe, which acts in parallel to omb. To explain the effects of omb alleles, we propose that both anterior and posterior compartments in the abdomen are polarized by underlying symmetric gradients of unknown origin. We suggest that omb has two functions. First, it specifies the development of appropriate structures both anterior and posterior to the compartment boundary. Second, it causes cells to reverse their interpretation of polarity specified by the underlying symmetric gradients.

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Sectors expressing the homeobox gene liguleless3 implicate a time-dependent mechanism for cell fate acquisition along the proximal-distal axis of the maize leaf

Development ◽

10.1242/dev.124.24.5097 ◽

1997 ◽

Vol 124 (24) ◽

pp. 5097-5106 ◽

Cited By ~ 13

Author(s):

G.J. Muehlbauer ◽

J.E. Fowler ◽

M. Freeling

Keyword(s):

Cell Fate ◽

Homeobox Gene ◽

Longitudinal Axis ◽

Cell Types ◽

Transverse Dimension ◽

Leaf Sheath ◽

Wild Type ◽

Cell Fates ◽

Maize Leaf ◽

Gradual Process

The longitudinal axis of the maize leaf is composed of, in proximal to distal order, sheath, ligule, auricle and blade. The semidominant Liguleless3-O (Lg3-O) mutation disrupts leaf development at the ligular region of the leaf midrib by transforming blade to sheath. In a previous study, we showed that leaf sectors of Lg3 mutant activity are cell nonautonomous in the transverse dimension and can confer several alternative developmental fates (Fowler, Muehlbauer and Freeling (1996) Genetics 143, 489–503). In our present study we identify five Lg3 sector types in the leaf: sheath-like with displaced ligule (sheath-like), sheath-like with ectopic ligule (ectopic ligule), auricle-like, macro-hairless blade and wild-type blade. The acquisition of a specific sector fate depends on the timing of Lg3 expression. Early Lg3 expression results in adoption of the sheath-like phenotype at the ligule position (a proximal cell fate), whereas later Lg3 expression at the same position results in one of the more distal cell fates. Furthermore, sheath-like Lg3 sectors exhibit a graded continuum of phenotypes in the transformed blade region from the most proximal (sheath) to the most distal (wild-type blade), suggesting that cell fate acquisition is a gradual process. We propose a model for leaf cell fate acquisition based on a timing mechanism whereby cells of the leaf primordium progress through a maturation schedule of competency stages which eventually specify the cell types along the proximal to distal axis of the leaf. In addition, the lateral borders between Lg3 ‘on’ sectors and wild-type leaf sometimes provide evidence of no spreading of the transformed phenotype. In these cases, competency stages are inherited somatically.

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Modifications of cell fate specification in equal-cleaving nemertean embryos: alternate patterns of spiralian development

Development ◽

10.1242/dev.121.10.3175 ◽

1995 ◽

Vol 121 (10) ◽

pp. 3175-3185 ◽

Cited By ~ 1

Author(s):

M.Q. Martindale ◽

J.Q. Henry

Keyword(s):

Cell Fate ◽

Cell Lineage ◽

Cell Types ◽

Embryonic Cell ◽

Specific Cell ◽

Cell Fate Specification ◽

Cell Fates ◽

Developmental Potential ◽

Fate Specification ◽

Symmetry Properties

The nemerteans belong to a phylum of coelomate worms that display a highly conserved pattern of cell divisions referred to as spiral cleavage. It has recently been shown that the fates of the four embryonic cell quadrants in two species of nemerteans are not homologous to those in other spiralian embryos, such as the annelids and molluscs (Henry, J. Q. and Martindale, M. Q. (1994a) Develop. Genetics 15, 64–78). Equal-cleaving molluscs utilize inductive interactions to establish quadrant-specific cell fates and embryonic symmetry properties following fifth cleavage. In order to elucidate the manner in which cell fates are established in nemertean embryos, we have conducted cell isolation and deletion experiments to examine the developmental potential of the early cleavage blastomeres of two equal-cleaving nemerteans, Nemertopsis bivittata and Cerebratulus lacteus. These two species display different modes of development: N. bivittata develops directly via a non-feeding larvae, while C. lacteus develops to form a feeding pilidium larva which undergoes a radical metamorphosis to give rise to the juvenile worm. By examining the development of certain structures and cell types characteristic of quadrant-specific fates for each of these species, we have shown that isolated blastomeres of the indirect-developing nemertean, C. lacteus, are capable of generating cell fates that are not a consequence of that cell's normal developmental program. For instance, dorsal blastomeres can form muscle fibers when cultured in isolation. In contrast, isolated blastomeres of the direct-developing species, N. bivittata do not regulate their development to the same extent. Some cell fates are specified in a precocious manner in this species, such as those that give rise to the eyes. Thus, these findings indicate that equal-cleaving spiralian embryos can utilize different mechanisms of cell fate and axis specification. The implications of these patterns of nemertean development are discussed in relation to experimental work in other spiralian embryos, and a model is presented that accounts for possible evolutionary changes in cell lineage and the process of cell fate specification amongst these protostome phyla.

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Single cell RNA-seq identifies developing corneal cell fates in the human cornea organoid

10.1101/2021.12.23.471999 ◽

2021 ◽

Author(s):

George Maiti ◽

Maithe Rocha Monteiro de Barros ◽

Nan Hu ◽

Mona Roshan ◽

Karl J Wahlin ◽

...

Keyword(s):

Single Cell ◽

Cell Fate ◽

Three Dimensional ◽

Cell Types ◽

Human Cornea ◽

Equal Proportion ◽

Fate Map ◽

Cell Fates ◽

Developmental States ◽

Induced Pluripotent

The cornea is a protective and refractive barrier in the eye crucial for vision. Understanding the human cornea in health, disease and cell-based treatments can be greatly advanced with cornea organoids developed in culture from induced pluripotent stem cells. While a limited number of studies have investigated the single-cell transcriptomic composition of the human cornea, its organoids have not been examined similarly. Here we elucidated the transcriptomic cell fate map of 4 month-old human cornea organoids and the central cornea from three donors. The organoids harbor cell clusters representing corneal epithelium, stroma and endothelium with sub populations that capture signatures of early developmental states. Unlike the adult cornea where the largest cell population is stromal, the organoids develop almost equal proportion of the three major cell types. These corneal organoids offer a three-dimensional platform to model corneal diseases and integrated responses of the different cell types to treatments.

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