Neurogenic and proneural genes control cell fate specification in the Drosophila endoderm

Development ◽  
1995 ◽  
Vol 121 (2) ◽  
pp. 393-405 ◽  
Author(s):  
U. Tepass ◽  
V. Hartenstein
Keyword(s):  
Epithelial Cells ◽  
Cell Fate ◽  
Interstitial Cell ◽  
Control Cell ◽  
Mesenchymal Cell ◽  
Gene Interaction ◽  
Cell Types ◽  
Midgut Epithelium ◽  
Specific Cell ◽  
Proneural Genes

The Drosophila endoderm segregates into three non-neural cell types, the principle midgut epithelial cells, the adult midgut precursors, and the interstitial cell precursors, early in development. We show that this process occurs in the absence of mesoderm and requires proneural and neurogenic genes. In neurogenic mutants the principle midgut epithelial cells are missing and the other two cell types develop in great excess. Consequently, the midgut epithelium does not form. In achaete-scute complex and daughterless mutants the interstitial cell precursors do not develop and the number of adult midgut precursors is strongly reduced. Development of the principle midgut epithelial cells and formation of the midgut epithelium is restored in neurogenic proneural double mutants. The neurogenic/proneural genes are, in contrast to the neuroectoderm, not expressed in small clusters of cells but initially homogeneously in the endoderm suggesting that no prepattern exists which determines the position of the segregating cells. Hence, the segregation pattern solely depends on neurogenic/proneural gene interaction. Proneural genes are required but not sufficient to determine specific cell fates because they are required for cell type specification in both ectoderm and endoderm. Our data also suggest that the neurogenic/proneural genes are involved in the choice between epithelial versus mesenchymal cell morphologies.

scholarly journals Histone Acetyltransferases and Stem Cell Identity

Cancers ◽  
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.

Analysis of lens cell fate and eye morphogenesis in transgenic mice ablated for cells of the lens lineage

Development ◽  
1989 ◽  
Vol 106 (3) ◽  
pp. 457-463 ◽  
Author(s):  
M.L. Breitman ◽  
D.M. Bryce ◽  
E. Giddens ◽  
S. Clapoff ◽  
D. Goring ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cell Fate ◽  
Vitreous Body ◽  
Cell Types ◽  
Ciliary Epithelium ◽  
Specific Cell ◽  
Promoter Sequences ◽  
Fiber Cells ◽  
Lens Cell ◽  
Diphtheria Toxin A

Transgenic mice carrying the diphtheria toxin A gene driven by mouse gamma 2-crystallin promoter sequences manifest microphthalmia due to ablation of fiber cells in the ocular lens. Here we map ablation events in the lens by crossing animals hemizygous for the ablation construct with transgenic mice homozygous for the in situ lacZ reporter gene driven by identical gamma 2-crystallin promoter sequences. By comparing the spatial distribution of lacZ-expressing cells and the profile of gamma-crystallin gene expression in the lenses of normal and microphthalmic offspring, the contributions of specific cell types to lens development were examined. The results suggest that phenotypically and developmentally distinct populations of lens fiber cells are able to contribute to the lens nucleus during organogenesis. We also show that dosage of the transgene and its site of integration influence the extent of ablation. In those mice homozygous for the transgene and completely lacking cells of the lens lineage, we show that the sclera, cornea, and ciliary epithelium are reduced in size but, otherwise, reasonably well formed. In contrast, the anterior chamber, iris, and vitreous body are not discernible while the sensory retina is highly convoluted and extensively fills the vitreous chamber.

Regulation of interstitial cell differentiation in Hydra attenuata. I. Homeostatic control of interstitial cell population size

1976 ◽  
Vol 20 (1) ◽  
pp. 29-46 ◽  
Author(s):  
H.R. Bode ◽  
K.M. Flick ◽  
G.S. Smith
Keyword(s):  
Cell Differentiation ◽  
Epithelial Cells ◽  
Population Size ◽  
Cell Population ◽  
Interstitial Cell ◽  
Normal Population ◽  
Cell Types ◽  
Hydra Attenuata ◽  
I Cells ◽  
Continuous Labelling

Mechanisms regulating the population size of the multipotent interstitial cell (i-cell) in Hydra attenuata were investigated. Treatment of animals with 3 cycles of a regime of 24 h in 10-2 M hydroxyurea (HU) alternated with 12 h in culture medium selectively killed 95–99% of the i-cells, but had little effect on the epithelial cells. The i-cell population recovered to the normal i-cell:epithelial cell ratio of I:I within 35 days. Continuous labelling experiments with [3H]thymidine indicate that the recovery of the i-cell population is not due to a change in the length of the cell cycle of either the epithelial cells or the interstitial cells. In control animals 60% of the i-cell population undergo division daily while 40% undergo differentiation. Quantification of the cell types of HU-treated animals indicates that a greater fraction of the i-cells were dividing and fewer differentiating into nematocytes during the first 2 weeks of the recovery after HU treatment. Therefore, the mechanism for recovery involves a shift of the 60:40 division:differentiation ratio of i-cells towards a higher fraction in division until the normal population size of the i-cells is regained. This homeostatic mechanism represents one of the influences affecting i-cell differentiation.

Vertebrate retinal ganglion cells are selected from competent progenitors by the action of Notch

Development ◽  
1995 ◽  
Vol 121 (11) ◽  
pp. 3637-3650 ◽  
Author(s):  
C.P. Austin ◽  
D.E. Feldman ◽  
J.A. Ida ◽  
C.L. Cepko
Keyword(s):  
Cell Fate ◽  
Ganglion Cells ◽  
Notch Pathway ◽  
Cell Types ◽  
Projection Neurons ◽  
Specific Cell ◽  
Vitro Assay ◽  
Notch Activity

The first cells generated during development of the vertebrate retina are the ganglion cells, the projection neurons of the retina. Although they are one of the most intensively studied cell types within the central nervous system, little is known of the mechanisms that determine ganglion cell fate. We demonstrate that ganglion cells are selected from a large group of competent progenitors that comprise the majority of the early embryonic retina and that differentiation within this group is regulated by Notch. Notch activity in vivo was diminished using antisense oligonucleotides or augmented using a retrovirally transduced constitutively active allele of Notch. The number of ganglion cells produced was inversely related to the level of Notch activity. In addition, the Notch ligand Delta inhibited retinal progenitors from differentiating as ganglion cells to the same degree as did activated Notch in an in vitro assay. These results suggest a conserved strategy for neurogenesis in the retina and describe a versatile in vitro and in vivo system with which to examine the action of the Notch pathway in a specific cell fate decision in a vertebrate.

scholarly journals Single-Cell RNA-seq Identifies Cell Diversity in Embryonic Salivary Glands

2019 ◽  
Vol 99 (1) ◽  
pp. 69-78 ◽  
Author(s):  
R. Sekiguchi ◽  
D. Martin ◽  
K.M. Yamada ◽  
Keyword(s):  
Epithelial Cells ◽  
Parotid Gland ◽  
Single Cell ◽  
Salivary Glands ◽  
Cell Fate ◽  
Mesenchymal Cell ◽  
Muscle Cells ◽  
Mesenchymal Cells ◽  
Organ Specificity ◽  
Bud Initiation

Branching organs, including the salivary and mammary glands, lung, and kidney, arise as epithelial buds that are morphologically very similar. However, the mesenchyme is known to guide epithelial morphogenesis and to help govern cell fate and eventual organ specificity. We performed single-cell transcriptome analyses of 14,441 cells from embryonic day 12 submandibular and parotid salivary glands to characterize their molecular identities during bud initiation. The mesenchymal cells were considerably more heterogeneous by clustering analysis than the epithelial cells. Nonetheless, distinct clusters were evident among even the epithelial cells, where unique molecular markers separated presumptive bud and duct cells. Mesenchymal cells formed separate, well-defined clusters specific to each gland. Neuronal and muscle cells of the 2 glands in particular showed different markers and localization patterns. Several gland-specific genes were characteristic of different rhombomeres. A muscle cluster was prominent in the parotid, which was not myoepithelial or vascular smooth muscle. Instead, the muscle cluster expressed genes that mediate skeletal muscle differentiation and function. Striated muscle was indeed found later in development surrounding the parotid gland. Distinct spatial localization patterns of neuronal and muscle cells in embryonic stages appear to foreshadow later differences in adult organ function. These findings demonstrate that the establishment of transcriptional identities emerges early in development, primarily in the mesenchyme of developing salivary glands. We present the first comprehensive description of molecular signatures that define specific cellular landmarks for the bud initiation stage, when the neural crest–derived ectomesenchyme predominates in the salivary mesenchyme that immediately surrounds the budding epithelium. We also provide the first transcriptome data for the largely understudied embryonic parotid gland as compared with the submandibular gland, focusing on the mesenchymal cell populations.

scholarly journals Single-Cell Transcriptomic Map of the Human and Mouse Bladders

2019 ◽  
Vol 30 (11) ◽  
pp. 2159-2176 ◽  
Author(s):  
Zhenyuan Yu ◽  
Jinling Liao ◽  
Yang Chen ◽  
Chunlin Zou ◽  
Haiying Zhang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Epithelial Cells ◽  
Single Cell ◽  
Cell Types ◽  
Specific Cell ◽  
Human Bladder ◽  
Healthy Human ◽  
Bladder Cell ◽  
Bladder Cells ◽  
Human And Mouse

BackgroundHaving a comprehensive map of the cellular anatomy of the normal human bladder is vital to understanding the cellular origins of benign bladder disease and bladder cancer.MethodsWe used single-cell RNA sequencing (scRNA-seq) of 12,423 cells from healthy human bladder tissue samples taken from patients with bladder cancer and 12,884 cells from mouse bladders to classify bladder cell types and their underlying functions.ResultsWe created a single-cell transcriptomic map of human and mouse bladders, including 16 clusters of human bladder cells and 15 clusters of mouse bladder cells. The homology and heterogeneity of human and mouse bladder cell types were compared and both conservative and heterogeneous aspects of human and mouse bladder evolution were identified. We also discovered two novel types of human bladder cells. One type is ADRA2A+ and HRH2+ interstitial cells which may be associated with nerve conduction and allergic reactions. The other type is TNNT1+ epithelial cells that may be involved with bladder emptying. We verify these TNNT1+ epithelial cells also occur in rat and mouse bladders.ConclusionsThis transcriptomic map provides a resource for studying bladder cell types, specific cell markers, signaling receptors, and genes that will help us to learn more about the relationship between bladder cell types and diseases.

scholarly journals Single-Cell Genomics: Catalyst for Cell Fate Engineering

2021 ◽  
Vol 9 ◽  
Author(s):  
Boxun Li ◽  
Gary C. Hon
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
State Transitions ◽  
Small Scale ◽  
Specific Cell ◽  
Direct Reprogramming ◽  
Cell State

As we near a complete catalog of mammalian cell types, the capability to engineer specific cell types on demand would transform biomedical research and regenerative medicine. However, the current pace of discovering new cell types far outstrips our ability to engineer them. One attractive strategy for cellular engineering is direct reprogramming, where induction of specific transcription factor (TF) cocktails orchestrates cell state transitions. Here, we review the foundational studies of TF-mediated reprogramming in the context of a general framework for cell fate engineering, which consists of: discovering new reprogramming cocktails, assessing engineered cells, and revealing molecular mechanisms. Traditional bulk reprogramming methods established a strong foundation for TF-mediated reprogramming, but were limited by their small scale and difficulty resolving cellular heterogeneity. Recently, single-cell technologies have overcome these challenges to rapidly accelerate progress in cell fate engineering. In the next decade, we anticipate that these tools will enable unprecedented control of cell state.

scholarly journals Ligand-receptor promiscuity enables cellular addressing

2020 ◽  
Author(s):  
Christina J. Su ◽  
Arvind Murugan ◽  
James M. Linton ◽  
Akshay Yeluri ◽  
Justin Bois ◽  
...  
Keyword(s):  
Cell Fate ◽  
Control Cell ◽  
Cell Communication ◽  
Biochemical Parameter ◽  
Cell Types ◽  
Receptor Expression ◽  
Modeling Framework ◽  
Morphogenetic Protein ◽  
Bmp Pathway ◽  
Fate Decision

AbstractIn multicellular organisms, secreted ligands selectively activate, or “address,” specific target cell populations to control cell fate decision-making and other processes. Key cell-cell communication pathways use multiple promiscuously interacting ligands and receptors, provoking the question of how addressing specificity can emerge from molecular promiscuity. To investigate this issue, we developed a general mathematical modeling framework based on the bone morphogenetic protein (BMP) pathway architecture. We find that promiscuously interacting ligand-receptor systems allow a small number of ligands, acting in combinations, to address a larger number of individual cell types, each defined by its receptor expression profile. Promiscuous systems outperform seemingly more specific one-to-one signaling architectures in addressing capacity. Combinatorial addressing extends to groups of cell types, is robust to receptor expression noise, grows more powerful with increasing receptor multiplicity, and is maximized by specific biochemical parameter relationships. Together, these results identify fundamental design principles governing cell addressing by ligand combinations.

scholarly journals A multiscale model of epigenetic heterogeneity reveals the kinetic routes of pathological cell fate reprogramming

2018 ◽  
Author(s):  
Núria Folguera-Blasco ◽  
Rubén Pérez-Carrasco ◽  
Elisabet Cuyás ◽  
Javier A. Menendez ◽  
Tomás Alarcón
Keyword(s):  
Stochastic Model ◽  
Cell Fate ◽  
Multiple Scales ◽  
Coupled System ◽  
Multiscale Model ◽  
Cell Types ◽  
Specific Cell ◽  
New Therapeutic Approaches ◽  
Correct Path

AbstractThe inherent capacity of somatic cells to switch their phenotypic status in response to damage stimuli in vivo might have a pivotal role in ageing and cancer. However, how the entry-exit mechanisms of phenotype reprogramming are established remains poorly understood. In an attempt to elucidate such mechanisms, we herein introduce a stochastic model of combined epigenetic regulation (ER)-gene regulatory network (GRN) to study the plastic phenotypic behaviours driven by ER heterogeneity. Furthermore, based on the existence of multiple scales, we formulate a method for stochastic model reduction, from which we derive an efficient hybrid simulation scheme that allows us to deal with such complex systems. Our analysis of the coupled system reveals a regime of tristability in which pluripotent stem-like and differentiated steady-states coexist with a third indecisive state. Crucially, ER heterogeneity of differentiation genes is for the most part responsible for conferring abnormal robustness to pluripotent stem-like states. We then formulate epigenetic heterogeneity-based strategies capable of unlocking and facilitating the transit from differentiation-refractory (pluripotent stem-like) to differentiation-primed epistates. The application of the hybrid numerical method validated the likelihood of such switching involving solely kinetic changes in epigenetic factors. Our results suggest that epigenetic heterogeneity regulates the mechanisms and kinetics of phenotypic robustness of cell fate reprogramming. The occurrence of tunable switches capable of modifying the nature of cell fate reprogramming from pathological to physiological might pave the way for new therapeutic strategies to regulate reparative reprogramming in ageing and cancer.Author summaryCertain modifications of the structure and functioning of the protein/DNA complex called chromatin can allow adult, fully differentiated cells to adopt a stem cell-like pluripotent state in a purely epigenetic manner, not involving changes in the underlying DNA sequence. Such reprogramming-like phenomena may constitute an innate reparative route through which human tissues respond to injury and could also serve as a novel regenerative strategy in human pathological situations in which tissue or organ repair is impaired. However, it should be noted that in vivo reprogramming would be capable of maintaining tissue homeostasis provided the acquisition of pluripotency features is strictly transient and accompanied by an accurate replenishment of the specific cell types being lost. Crucially, an excessive reprogramming to pluripotency in the absence of controlled re-differentiation would impair the repair or the replacement of damaged cells, thereby promoting pathological alterations of cell fate. A mechanistic understanding of how the degree of chromatin plasticity dictates the reparative versus pathological behaviour of in vivo reprogramming to rejuvenate aged tissues while preventing tumorigenesis is urgently needed, including especially the intrinsic epigenetic heterogeneity of the tissue resident cells being reprogrammed. We here introduce a novel method that mathematically captures how epigenetic heterogeneity is actually the driving force that governs the routes and kinetics to entry into and exit from a pathological pluripotent-like state. Moreover, our approach computationally validates the likelihood of unlocking chronic, unrestrained pluripotent states and drive their differentiation down the correct path by solely manipulating the intensity and direction of few epigenetic control switches. Our approach could inspire new therapeutic approaches based on in vivo cell reprogramming for efficient tissue regeneration and rejuvenation and cancer treatment.

Ezrin is concentrated in the apical microvilli of a wide variety of epithelial cells whereas moesin is found primarily in endothelial cells

1993 ◽  
Vol 105 (4) ◽  
pp. 1025-1043 ◽  
Author(s):  
M. Berryman ◽  
Z. Franck ◽  
A. Bretscher
Keyword(s):  
Endothelial Cells ◽  
Epithelial Cells ◽  
Cultured Cells ◽  
Cell Types ◽  
Cytoskeletal Proteins ◽  
Specific Cell ◽  
Apical Surface ◽  
Tissue Sections ◽  
Differentiated Cells

Ezrin and moesin are two cytoskeletal proteins originally purified from human placenta that are 74% identical in overall protein sequence. They are believed to be membrane-cytoskeletal linking proteins because they share sequence homology with erythrocyte band 4.1 and colocalize with actin specifically in microvilli and membrane ruffles in cultured cells. To determine if ezrin and moesin share similar distributions in vivo, we studied their localizations with respect to F-actin in tissue sections. Surprisingly, ezrin and moesin exhibited very different cellular distributions. Ezrin was highly concentrated and colocalized with actin on the apical surface of many epithelial cell types. During enterocyte differentiation, the pattern of expression and redistribution of ezrin was consistent with it performing a role in microvillus assembly. Immunoelectron microscopy in differentiated cells revealed that ezrin was restricted mainly to the plasma membrane of microvilli and other actin-rich surface projections. Moesin was found in endothelial cells and was also enriched in the apical microvilli of a restricted set of epithelial cells. All polarized cell types with abundant microvilli contained one or both proteins, suggesting that ezrin and moesin perform related functions. However, the differential expression of ezrin and moesin indicates that they have distinct properties, which are uniquely adapted to specific cell types.

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