Fate Proliferation Research Articles

Via das pentoses fosfato e síntese de fosfolipídios como futuro tratamento do câncer: uma revisão sistemática

Entender o equilíbrio celular e interferência no destino proliferativo torna a via das pentoses fosfato um alvo essencial nos processos metabólicos. O objetivo deste trabalho foi revisar nos periódicos científicos indícios e fundamentações para bloquear a via das pentoses fosfato como prática alternativa no tratamento de neoplasia. Essa revisão foi desenvolvida a partir de uma revisão exploratória de artigos selecionados nas plataformas de base de dados da Literatura Latino-americana e do Caribe em Ciências da Saúde (Lilacs), e Scientific Eletronic Libray Online (SciELO), Medical Literature Analysis and Retrieval Sistem Online (MedLine) e Google Acadêmico, cujos documentos são cruciais para levantar propostas que o tema tem por objetivo. Os estudos revisados neste artigo, demonstraram resultados positivos e de grande importância para a atividade da via das pentoses fosfato. Ao se pensar em reprogramação metabólica, obtemos uma ligação significativa relacionada ao câncer, e os mecanismos que as células utilizam para suportar ambientes com intensas necessidades energéticas e o envolvimento da atividade da via PPP, ainda precisam ser melhor compreendido, tendo em vista que, pode ser regulada positivamente no câncer e se tornar um alvo atrativo em busca de prognósticos de tumores e definir novos tratamentos oncológicos.

CARF promotes spermatogonial self-renewal and proliferation through Wnt signaling pathway

Collaborator of ARF (CARF) regulates cell proliferative fate through both p53-dependent and -independent mechanisms. Recently, we reported a new function of CARF as a positive regulator of Wnt signaling. Despite these findings, the physiological function of CARF has not been well studied. Here, we generated CARF knockout mice and found that male CARF−/− mice exhibited significantly impaired fertility and Sertoli-cell-only (SCO) syndrome phenotypes. Further studies revealed that loss of CARF in Sertoli cells led to decreased GDNF expression, which hindered spermatogonial stem cells (SSCs) self-renewal. Meanwhile, CARF loss in undifferentiated spermatogonia impaired their proliferation. These two mechanisms together led to SCO syndrome phenotypes, which could be functionally rescued by pharmacological or genetic reactivation of Wnt signaling. Finally, we identified CARFS351F as a potential pathogenic mutation in an SCO patient. Overall, our findings reveal important roles of CARF in spermatogonial self-renewal and proliferation through the Wnt signaling pathway.

Proteotoxic Stress and Cell Death in Cancer Cells.

To maintain proteostasis, cells must integrate information and activities that supervise protein synthesis, protein folding, conformational stability, and also protein degradation. Extrinsic and intrinsic conditions can both impact normal proteostasis, causing the appearance of proteotoxic stress. Initially, proteotoxic stress elicits adaptive responses aimed at restoring proteostasis, allowing cells to survive the stress condition. However, if the proteostasis restoration fails, a permanent and sustained proteotoxic stress can be deleterious, and cell death ensues. Many cancer cells convive with high levels of proteotoxic stress, and this condition could be exploited from a therapeutic perspective. Understanding the cell death pathways engaged by proteotoxic stress is instrumental to better hijack the proliferative fate of cancer cells.

The Molecular Anatomy of Mouse Skin during Hair Growth and Rest.

Skin homeostasis is orchestrated by dozens of cell types that together direct stem cell renewal, lineage commitment, and differentiation. Here, we use single-cell RNA sequencing and single-molecule RNA FISH to provide a systematic molecular atlas of full-thickness skin, determining gene expression profiles and spatial locations that define 56 cell types and states during hair growth and rest. These findings reveal how the outer root sheath (ORS) and inner hair follicle layers coordinate hair production. We found that the ORS is composed of two intermingling but transcriptionally distinct cell types with differing capacities for interactions with stromal cell types. Inner layer cells branch from transcriptionally uncommitted progenitors, and each lineage differentiation passes through an intermediate state. We also provide an online tool to explore this comprehensive skin cell atlas, including epithelial and stromal cells such as fibroblasts, vascular, and immune cells, to spur further discoveries in skin biology.

Abstract P166: Paracrine Endothelial Microrna214 Exosomes Modulate Smooth Muscle Cell Function in Pulmonary Arterial Hypertension

Background: Communication among various cell types is known to play a pivotal role in PAH. Endothelial cell (EC)-derived exosomes have emerged as important mediators of intercellular communication and are known to influence the function of recipient cells. A role for miR-214 in EC-derived exosomes in PAH, however, is entirely unknown. In this study, we hypothesize that hypoxia-induced EC injury releases exosomes enriched in miR-214 that mediates phenotype switching of smooth muscle cells (SMCs) resulting in increased SMC proliferation in PAH. Methods and Results: We subjected human pulmonary artery endothelial cells (hPAECs) to hypoxia vs. normoxia (norm) to recapitulate the PAH phenotype in vitro . Quantitative RT-PCR of hPAECs showed that hypoxia upregulated miR-214 by 1.51±0.24-fold (p<0.05 vs. norm). Moreover, exosomes derived from hypoxic hPAECs were found to be enriched in miR-214 (1.73±0.16-fold vs. norm, p<0.05). TEM and Nanotracking Analysis System determined the size of EC-derived exosomes to be within a characteristic 30-100nm. Furthermore, Z-stack confocal imaging demonstrated that FITC-PHK67-labeled EC-derived exosomes were taken up by hPASMCs. Western blot of hPASMCs treated with hypoxia-induced EC-derived exosomes showed upregulation of phospho-Akt (1.65±0.29-fold vs. norm, p <0.05), phospho-ERK1/2 (1.68±0.27-fold vs. norm, p <0.05), and Bcl2 (1.63±0.19-fold vs. norm, NS). Similar treatment also decreased SMC-specific genes, such as MYH11, calponin and smoothelin, indicating that EC-derived hypoxic exosomes can induce switching of PASMCs to a synthetic, pro-proliferative phenotype. Moreover, scratch assay demonstrated that application of EC-derived exosomes laden with exogenous miR-214 increased SMC migration (1.28±0.08-fold vs. control, p =0.05). Conclusions & Discussion: We found that miR-214 expression was induced in hypoxia both in ECs and in exosomes released from them. Furthermore, EC-derived hypoxic or miR-214-laden exosomes were able to transduce changes in SMC, which result in a proliferative and synthetic phenotype. These findings demonstrate that EC-derived miR-214 can direct a proliferative fate for smooth muscle cells, and may contribute to SMC-associated pathophysiological changes in PAH.

188-OR: Partial Depletion of CD206 M2-Like Macrophages Enhances Preadipocyte Differentiation via Reduction of Wnt Signaling

Several pieces of evidence indicate that Wnt/β-catenin pathway may regulate the mesenchymal stem cells fate proliferation in vivo. The Wnt signaling is also known to inhibit preadipocyte differentiation into adipocyte. Adipose tissue macrophages play important roles in the maintenance of tissue homeostasis by regulating insulin sensitivity via their anti-inflammatory actions. However, how CD206 M2-like macrophages linked to Wnt signaling in maintaining the preadipocyte differentiation, remains elusive. In the present study, we aimed to investigate the physiological role of CD206 linked to Wnt signaling in preadipocyte differentiation. We show that C1q, which can mediate Wnt signaling, is abundantly expressed in CD206 M2-like macrophages in epididymal adipose tissue. Then, we examined whether CD206 M2-macrophages depletion activate or inhibit Wnt signaling and preadipocyte differentiation. Here, we show that the expression of M2 marker genes was reduced with a reduced expression of Wnt signaling genes in adipose tissue of CD206-reduced mice. Western blot analysis confirmed reduced protein level of β-catenin in CD206-reduced mice that can contribute to regulate the preadipocyte/progenitor’s activity. We presumed that the reduction of C1q-induced Wnt signaling promoted adipogenesis. We also found that depletion of CD206 M2-like macrophages resulted in the generation of the smaller adipocyte, upregulated expression of metabolically favorable genes and enhanced insulin sensitivity in both chow and high-fat diet-fed CD206-reduced mice. Taken together, we show that partial depletion of CD206 M2-like macrophages inhibits Wnt/β-catenin pathway activity in mice and increases preadipocyte differentiation, thus ameliorating insulin resistance in lean and obese mice. Disclosure A. Nawaz: Research Support; Spouse/Partner; Astellas Pharma Inc., Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company. Research Support; Self; Japan Society for the Promotion of Science. Research Support; Spouse/Partner; Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Shionogi & Co., Ltd., Takeda Pharmaceutical Company Limited. T. Nakagawa: None. K. Yagi: None. S. Fujisaka: None. K. Tobe: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Japan Diabetes Society. Research Support; Self; Bristol-Myers Squibb Company. K. Okabe: None. T. Kado: None. J. Liu: None. M. Bilal: None. Funding Japan Society for the Promotion of Science

EMT and Stemness in Tumor Dormancy and Outgrowth: Are They Intertwined Processes?

Metastases are the major cause of cancer patients' mortality and can occur years and even decades following apparently successful treatment of the primary tumor. Early dissemination of cancer cells, followed by a protracted period of dormancy at distant sites, has been recently recognized as the clinical explanation for this very-long latency. The mechanisms that govern tumor dormancy at distant sites and their reactivation to proliferating metastases are just beginning to be unraveled. Tumor cells, that survive the immune surveillance and hemodynamic forces along their journey in the circulation and successfully colonize and adopt to the new and “hostile” microenvironment and survive in a quiescent dormant state for years before emerging to proliferative state, must display high plasticity. Here we will discuss whether the plasticity of dormant tumor cells is required for their long-term survival and outgrowth. Specifically, we will focus on whether epithelial mesenchymal transition and acquisition of stem-like properties can dictate their quiescent and or their proliferative fate. Deeper understanding of these intertwining processes may facilitate in the future the development of novel therapies.

Lgr5+ intestinal stem cells reside in an unlicensed G1 phase.

During late mitosis and the early G1 phase, the origins of replication are licensed by binding to double hexamers of MCM2-7. In this study, we investigated how licensing and proliferative commitment are coupled in the epithelium of the small intestine. We developed a method for identifying cells in intact tissue containing DNA-bound MCM2-7. Interphase cells above the transit-amplifying compartment had no DNA-bound MCM2-7, but still expressed the MCM2-7 protein, suggesting that licensing is inhibited immediately upon differentiation. Strikingly, we found most proliferative Lgr5+ stem cells are in an unlicensed state. This suggests that the elongated cell-cycle of intestinal stem cells is caused by an increased G1 length, characterized by dormant periods with unlicensed origins. Significantly, the unlicensed state is lost in Apc-mutant epithelium, which lacks a functional restriction point, causing licensing immediately upon G1 entry. We propose that the unlicensed G1 phase of intestinal stem cells creates a temporal window when proliferative fate decisions can be made.

Epidermal Wnt signalling regulates transcriptome heterogeneity and proliferative fate in neighbouring cells

BackgroundCanonical Wnt/beta-catenin signalling regulates self-renewal and lineage selection within the mammalian epidermis. Although the transcriptional response of keratinocytes that receive a Wnt signal is well characterized, little is known about the mechanism by which keratinocytes in proximity to the Wnt-receiving cell are co-opted to undergo a change in cell fate.ResultsTo address this, we perform single-cell RNA-sequencing on mouse keratinocytes co-cultured with and without beta-catenin-activated neighbouring cells. We identify five distinct cell states in cultures that had not been exposed to the beta-catenin stimulus and show that the stimulus redistributes wild-type subpopulation proportions. Using temporal single-cell analysis, we reconstruct the cell fate change induced by Wnt activation from neighbouring cells. Gene expression heterogeneity is reduced in neighbouring cells and this effect is most dramatic for protein synthesis-associated genes. Changes in gene expression are accompanied by a shift to a more proliferative stem cell state. By integrating imaging and reconstructed sequential gene expression changes during the state transition we identify transcription factors, including Smad4 and Bcl3, that are responsible for effecting the transition in a contact-dependent manner.ConclusionsOur data indicate that non-cell autonomous Wnt/beta-catenin signalling decreases transcriptional heterogeneity. This furthers our understanding of how epidermal Wnt signalling orchestrates regeneration and self-renewal.

DNA Barcoding Reveals Habitual Clonal Dominance of Myeloma Plasma Cells in the Bone Marrow Microenvironment

Multiple myeloma (MM) is a hematological malignancy resulting from the uncontrolled proliferation of antibody-producing plasma cells in the bone marrow. At diagnosis, independent plasma cell tumors are found throughout the skeleton. The recirculation of mutant plasma cells from the initial lesion and their recolonization of distant marrow sites are thought to occur by a process similar to solid tumor metastasis. However, the efficiency of this bone marrow homing process and the proportion of disseminated cells that actively divide and contribute to new tumor growth in MM are both unknown. We used the C57BL/KaLwRij mouse model of myeloma, lentiviral-mediated DNA barcoding of 5TGM1 myeloma cells, and next-generation sequencing to investigate the relative efficiency of plasma cell migration to, and growth within, the bone marrow. This approach revealed three major findings: firstly, establishment of metastasis within the bone marrow was extremely inefficient, with approximately 0.01% of circulating myeloma cells becoming resident long term in the bone marrow of each long bone; secondly, the individual cells of each metastasis exhibited marked differences in their proliferative fates, with the majority of final tumor burden within a bone being attributable to the progeny of between 1 and 8 cells; and, thirdly, the proliferative fate of individual clonal plasma cells differed at each bone marrow site in which the cells “landed.” These findings suggest that individual myeloma plasma cells are subjected to vastly different selection pressures within the bone marrow microenvironment, highlighting the importance of niche-driven factors, which determine the disease course and outcome.

Combined changes in Wnt signaling response and contact inhibition induce altered proliferation in radiation-treated intestinal crypts.

Curative intervention is possible if colorectal cancer is identified early, underscoring the need to detect the earliest stages of malignant transformation. A candidate biomarker is the expanded proliferative zone observed in crypts before adenoma formation, also found in irradiated crypts. However, the underlying driving mechanism for this is not known. Wnt signaling is a key regulator of proliferation, and elevated Wnt signaling is implicated in cancer. Nonetheless, how cells differentiate Wnt signals of varying strengths is not understood. We use computational modeling to compare alternative hypotheses about how Wnt signaling and contact inhibition affect proliferation. Direct comparison of simulations with published experimental data revealed that the model that best reproduces proliferation patterns in normal crypts stipulates that proliferative fate and cell cycle duration are set by the Wnt stimulus experienced at birth. The model also showed that the broadened proliferation zone induced by tumorigenic radiation can be attributed to cells responding to lower Wnt concentrations and dividing at smaller volumes. Application of the model to data from irradiated crypts after an extended recovery period permitted deductions about the extent of the initial insult. Application of computational modeling to experimental data revealed how mechanisms that control cell dynamics are altered at the earliest stages of carcinogenesis.

Proteasome regulation of the chromodomain protein MRG-1 controls the balance between proliferative fate and differentiation in the C. elegans germ line.

The level of stem cell proliferation must be tightly controlled for proper development and tissue homeostasis. Multiple levels of gene regulation are often employed to regulate stem cell proliferation to ensure that the amount of proliferation is aligned with the needs of the tissue. Here we focus on proteasome-mediated protein degradation as a means of regulating the activities of proteins involved in controlling the stem cell proliferative fate in the C. elegans germ line. We identify five potential E3 ubiquitin ligases, including the RFP-1 RING finger protein, as being involved in regulating proliferative fate. RFP-1 binds to MRG-1, a homologue of the mammalian chromodomain-containing protein MRG15 (MORF4L1), which has been implicated in promoting the proliferation of neural precursor cells. We find that C. elegans with reduced proteasome activity, or that lack RFP-1 expression, have increased levels of MRG-1 and a shift towards increased proliferation in sensitized genetic backgrounds. Likewise, reduction of MRG-1 partially suppresses stem cell overproliferation. MRG-1 levels are controlled independently of the spatially regulated GLP-1/Notch signalling pathway, which is the primary signal controlling the extent of stem cell proliferation in the C. elegans germ line. We propose a model in which MRG-1 levels are controlled, at least in part, by the proteasome, and that the levels of MRG-1 set a threshold upon which other spatially regulated factors act in order to control the balance between the proliferative fate and differentiation in the C. elegans germ line.

Collaborator of ARF (CARF) Regulates Proliferative Fate of Human Cells by Dose-dependent Regulation of DNA Damage Signaling

Collaborator of ARF (CARF) has been shown to directly bind to and regulate p53, a central protein that controls tumor suppression via cellular senescence and apoptosis. However, the cellular functions of CARF and the mechanisms governing its effect on senescence, apoptosis, or proliferation are still unknown. Our previous studies have shown that (i) CARF is up-regulated during replicative and stress-induced senescence, and its exogenous overexpression caused senescence-like growth arrest of cells, and (ii) suppression of CARF induces aneuploidy, DNA damage, and mitotic catastrophe, resulting in apoptosis via the ATR/CHK1 pathway. In the present study, we dissected the cellular role of CARF by investigating the molecular pathways triggered by its overexpression in vitro and in vivo. We found that the dosage of CARF is a critical factor in determining the proliferation potential of cancer cells. Most surprisingly, although a moderate level of CARF overexpression induced senescence, a very high level of CARF resulted in increased cell proliferation. We demonstrate that the level of CARF is crucial for DNA damage and checkpoint response of cells through ATM/CHK1/CHK2, p53, and ERK pathways that in turn determine the proliferative fate of cancer cells toward growth arrest or proproliferative and malignant phenotypes. To the best of our knowledge, this is the first report that demonstrates the capability of a fundamental protein, CARF, in controlling cell proliferation in two opposite directions and hence may play a key role in tumor biology and cancer therapeutics.

Brachyury regulates proliferation of cancer cells via a p27Kip1-dependent pathway.

The T-box transcription factor Brachyury is expressed in a number of tumour types and has been demonstrated to have cancer inducing properties. To date, it has been linked to cancer associated induction of epithelial to mesenchymal transition, tumour metastasis and expression of markers for cancer stem-like cells. Taken together, these findings indicate that Brachyury plays an important role in the progression of cancer, although the mechanism through which it functions is poorly understood. Here we show that Brachyury regulates the potential of Brachyury-positive colorectal cancer cells to proliferate and reduced levels of Brachyury result in inhibition of proliferation, with features consistent with the cells entering a quiescent-like state. This inhibition of proliferation is dependent upon p27Kip1 demonstrating that Brachyury acts to modulate cellular proliferative fate in colorectal cancer cells in a p27Kip1-dependent manner. Analysis of patient derived colorectal tumours reveals a heterogeneous localisation of Brachyury (in the nucleolus, nucleus and cytoplasm) indicating the potential complexity of the regulatory role of Brachyury in solid colorectal tumours.

Protein kinase CK2 both promotes robust proliferation and inhibits the proliferative fate in the C. elegans germ line

Stem cells are capable of both self-renewal (proliferation) and differentiation. Determining the regulatory mechanisms controlling the balance between stem cell proliferation and differentiation is not only an important biological question, but also holds the key for using stem cells as therapeutic agents. The Caenorhabditis elegans germ line has emerged as a valuable model to study the molecular mechanisms controlling stem cell behavior. In this study, we describe a large-scale RNAi screen that identified kin-10, which encodes the β subunit of protein kinase CK2, as a novel factor regulating stem cell proliferation in the C. elegans germ line. While a loss of kin-10 in an otherwise wild-type background results in a decrease in the number of proliferative cells, loss of kin-10 in sensitized genetic backgrounds results in a germline tumor. Therefore, kin-10 is not only necessary for robust proliferation, it also inhibits the proliferative fate. We found that kin-10’s regulatory role in inhibiting the proliferative fate is carried out through the CK2 holoenzyme, rather than through a holoenzyme-independent function, and that it functions downstream of GLP-1/Notch signaling. We propose that a loss of kin-10 leads to a defect in CK2 phosphorylation of its downstream targets, resulting in abnormal activity of target protein(s) that are involved in the proliferative fate vs. differentiation decision. This eventually causes a shift towards the proliferative fate in the stem cell fate decision.

The role of FGF2 in spinal cord trauma and regeneration research

The role of <scp>FGF</scp>2 in spinal cord trauma and regeneration research

PUF-8 negatively regulates RAS/MAPK signalling to promote differentiation of C. elegans germ cells.

Signals that promote germ cell self-renewal by preventing premature meiotic entry are well understood. However, signals that control mitotic proliferation to promote meiotic differentiation have not been well characterized. In Caenorhabditis elegans, GLP-1 Notch signalling promotes the proliferative fate by preventing premature meiotic entry. The germline niche cell, which is the source of the ligand for GLP-1, spatially restricts GLP-1 signalling and thus enables the germ cells that have moved away from the niche to enter meiosis. Here, we show that the suppression of RAS/MAP kinase signalling in the mitotic and meiotic-entry regions is essential for the regulation of the mitosis-meiosis switch by niche signalling. We provide evidence that the conserved PUF family RNA-binding protein PUF-8 and the RAS GAP protein GAP-3 function redundantly to suppress the LET-60 RAS in the mitotic and meiotic entry regions. Germ cells missing both PUF-8 and GAP-3 proliferate in an uncontrolled fashion and fail to undergo meiotic development. MPK-1, the MAP kinase downstream of the LET-60 RAS, is prematurely activated in these cells; downregulation of MPK-1 activation eliminates tumours and restores differentiation. Our results further reveal that PUF-8 negatively regulates LET-60 expression at a post-transcriptional step. LET-60 is misexpressed in the puf-8(-) mutant germlines and PUF-8 physically interacts with the let-60 3′ UTR. Furthermore, PUF-8 suppresses let-60 3′ UTR-mediated expression in the germ cells that are transitioning from the mitotic to meiotic fate. These results reveal that PUF-8-mediated inhibition of the RAS/MAPK pathway is essential for mitotic-to-meiotic fate transition.

PUF-8, a Pumilio Homolog, Inhibits the Proliferative Fate in theCaenorhabditis elegansGermline

Stem cell populations are maintained by keeping a balance between self-renewal (proliferation) and differentiation of dividing stem cells. Within the Caenorhabditis elegans germline, the key regulator maintaining this balance is the canonical Notch signaling pathway, with GLP-1/Notch activity promoting the proliferative fate. We identified the Pumilio homolog, PUF-8, as an inhibitor of the proliferative fate of stem cells in the C. elegans germline. puf-8(0) strongly enhances overproliferation of glp-1(gf) mutants and partially suppresses underproliferation of a weak glp-1(lf) mutant. The germline tumor that is formed in a puf-8(0); glp-1(gf) double mutant is due to a failure of germ cells to enter meiotic prophase. puf-8 likely inhibits the proliferative fate through negatively regulating GLP-1/Notch signaling or by functioning parallel to it.

Stem cell proliferation versus meiotic fate decision in Caenorhabditis elegans.

The C. elegans germ line has emerged as an important model for -understanding how a stem cell population is maintained throughout the life of the animal while still producing the gametes necessary for propagation of the species. The stem cell population in the adult hermaphrodite is relatively large, with stem cells giving rise to daughters that appear intrinsically equivalent; however, some of the daughters retain the proliferative fate while others enter meiotic prophase. While machinery exists for cells to progress through the mitotic cell cycle and machinery exists for cells to progress through meiotic prophase, central to understanding germ line development is identifying the genes and regulatory processes that determine whether the mitotic cell cycle or meiotic prophase machinery will be utilized; in other words, the genes that regulate the switch of germ cells from the proliferative stem cell fate to the meiotic development fate. Whether a germ cell self-renews or enters meiotic prophase is largely determined by its proximity to the distal tip cell (DTC), which is the somatic niche cell that caps the distal end of the gonad. Germ cells close to the DTC have high levels of GLP-1 Notch signaling, which promotes the proliferative fate, while cells further from the DTC have high activity levels of the GLD-1 and GLD-2 redundant RNA regulatory pathways, as well as a third uncharacterized pathway, each of which direct cells to enter meiotic prophase. Other factors and pathways modulate this core genetic pathway, or work in parallel to it, presumably to ensure that a tight balance is maintained between proliferation and meiotic entry.

Introduction to germ cell development in Caenorhabditis elegans.

A central feature of the continuum of life in sexually reproducing metazoans is the cycle of the germline from one generation to the next. This volume describes the cycle of the germline for Caenorhabditis elegans through chapters that are focused on distinct aspects or processes in germ cell development. Topics include sequential and dependent processes such as specification of germ cells as distinct from somatic cells, sex determination, stem cell proliferative fate versus meiotic development decision, recombination/progression through meiotic prophase, contemporaneous processes such as gametogenesis, meiotic development and apoptosis, and continuing the cycle into the next generation through fertilization and the oocyte-to-embryo transition. Throughout germ cell development, translational control and epigenetic mechanisms play prominent roles. These different aspects of germ cell development are seamlessly integrated under optimal conditions and are modified in the different reproductive strategies that are employed by C. elegans under harsh environmental conditions. In this chapter, we set the stage by providing a brief background on the C. elegans system and germ cell development, indicating processes in the cycle of the germline that are covered in each chapter.