scholarly journals Identifying Molecular Chechkpoints for Adventitious Root Induction: Are We Ready to Fill the Gaps?

2021 ◽  
Vol 12 ◽  
Author(s):  
Dolores Abarca
Keyword(s):  
Cell Proliferation ◽  
Cell Fate ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Adventitious Rooting ◽  
Hormonal Control ◽  
Limiting Factors ◽  
Root Induction ◽  
Long Distance

The molecular mechanisms underlying de novo root organogenesis have been under intense study for the last decades. As new tools and resources became available, a comprehensive model connecting the processes and factors involved was developed. Separate phases that allow for specific analyses of individual checkpoints were well defined. Physiological approaches provided information on the importance of metabolic processes and long-distance signaling to balance leaf and stem status and activation of stem cell niches to form new root meristems. The study of plant hormones revealed a series of sequential roles for cytokinin and auxin, dynamically interconnected and modulated by jasmonic acid and ethylene. The identification of genes specifying cell identity uncovered a network of sequentially acting transcriptional regulators that link hormonal control to cell fate respecification. Combined results from herbaceous model plants and the study of recalcitrant woody species underscored the need to understand the limiting factors that determine adventitious rooting competence. The relevance of epigenetic control was emphasized by the identification of microRNAs and chromatin remodeling agents involved in the process. As the different players are set in place and missing pieces become apparent, findings in related processes can be used to identify new candidates to complete the picture. Molecular knobs connecting the balance cell proliferation/differentiation to hormone signaling pathways, transcriptional control of cell fate or metabolic modulation of developmental programs can offer clues to unveil new elements in the dynamics of adventitious rooting regulatory networks. Mechanisms for cell non-autonomous signaling that are well characterized in other developmental processes requiring establishment and maintenance of meristems, control of cell proliferation and cell fate specification can be further explored. Here, we discuss possible candidates and approaches to address or elude the limitations that hinder propagation programs requiring adventitious rooting.

scholarly journals Gene regulatory networks controlling differentiation, survival, and diversification of hypothalamic Lhx6-expressing GABAergic neurons

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Dong Won Kim ◽  
Kai Liu ◽  
Zoe Qianyi Wang ◽  
Yi Stephanie Zhang ◽  
Abhijith Bathini ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Gabaergic Neurons ◽  
Zona Incerta ◽  
Long Distance ◽  
Hypothalamic Neurons ◽  
Cortical Interneuron ◽  
Tangential Migration ◽  
Innate Behaviors

AbstractGABAergic neurons of the hypothalamus regulate many innate behaviors, but little is known about the mechanisms that control their development. We previously identified hypothalamic neurons that express the LIM homeodomain transcription factor Lhx6, a master regulator of cortical interneuron development, as sleep-promoting. In contrast to telencephalic interneurons, hypothalamic Lhx6 neurons do not undergo long-distance tangential migration and do not express cortical interneuronal markers such as Pvalb. Here, we show that Lhx6 is necessary for the survival of hypothalamic neurons. Dlx1/2, Nkx2-2, and Nkx2-1 are each required for specification of spatially distinct subsets of hypothalamic Lhx6 neurons, and that Nkx2-2+/Lhx6+ neurons of the zona incerta are responsive to sleep pressure. We further identify multiple neuropeptides that are enriched in spatially segregated subsets of hypothalamic Lhx6 neurons, and that are distinct from those seen in cortical neurons. These findings identify common and divergent molecular mechanisms by which Lhx6 controls the development of GABAergic neurons in the hypothalamus.

scholarly journals Shaping of Drosophila Neural Cell Lineages Through Coordination of Cell Proliferation and Cell Fate by the BTB-ZF Transcription Factor Tramtrack-69

Genetics ◽  
2019 ◽  
Vol 212 (3) ◽  
pp. 773-788
Author(s):  
Françoise Simon ◽  
Anne Ramat ◽  
Sophie Louvet-Vallée ◽  
Jérôme Lacoste ◽  
Angélique Burg ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Cell Fate ◽  
Zinc Finger ◽  
Molecular Mechanisms ◽  
Neural Cell ◽  
Cell Cycle Exit ◽  
Cell Lineages ◽  
Accessory Cells

Cell diversity in multicellular organisms relies on coordination between cell proliferation and the acquisition of cell identity. The equilibrium between these two processes is essential to assure the correct number of determined cells at a given time at a given place. Using genetic approaches and correlative microscopy, we show that Tramtrack-69 (Ttk69, a Broad-complex, Tramtrack and Bric-à-brac - Zinc Finger (BTB-ZF) transcription factor ortholog of the human promyelocytic leukemia zinc finger factor) plays an essential role in controlling this balance. In the Drosophila bristle cell lineage, which produces the external sensory organs composed by a neuron and accessory cells, we show that ttk69 loss-of-function leads to supplementary neural-type cells at the expense of accessory cells. Our data indicate that Ttk69 (1) promotes cell cycle exit of newborn terminal cells by downregulating CycE, the principal cyclin involved in S-phase entry, and (2) regulates cell-fate acquisition and terminal differentiation, by downregulating the expression of hamlet and upregulating that of Suppressor of Hairless, two transcription factors involved in neural-fate acquisition and accessory cell differentiation, respectively. Thus, Ttk69 plays a central role in shaping neural cell lineages by integrating molecular mechanisms that regulate progenitor cell cycle exit and cell-fate commitment.

scholarly journals MON-719 The Cellular and Molecular Landscape of Hypothalamic Patterning and Differentiation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Thomas Kim
Keyword(s):  
Cell Fate ◽  
Regulatory Networks ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Brain Atlas ◽  
Specific Gene ◽  
Cell Fate Specification ◽  
Human Hypothalamus ◽  
Fate Specification ◽  
Time Points

Abstract The hypothalamus is a central regulator of physiological homeostasis. During development, multiple transcription factors coordinate the patterning and specification of hypothalamic nuclei. However, the molecular mechanisms controlling hypothalamic patterning and cell fate specification are poorly understood. To identify genes that control these processes, we have used single-cell RNA sequencing (scRNA-Seq) to profile mouse hypothalamic gene expression across multiple developmental time points. We have further utilised scRNA-Seq to phenotype mutations in genes that play major roles in early hypothalamic patterning. To first understand hypothalamic development, hypothalami were collected at both embryonic (E10-E16, E18) and postnatal (PN4, PN8, PN14, PN45) time points. At early stages, when the bulk of hypothalamic patterning occurs (E11-E13), we observe a clear separation between mitotic progenitors and postmitotic neural precursor cells. We likewise observed clean segregation among cells expressing regional hypothalamic markers identified in previous large-scale analysis of hypothalamic development. This analysis reveals new region-specific markers and identifies candidate genes for selectively regulating patterning and cell fate specification in individual hypothalamic regions. With our rich dataset of developing mouse hypothalamus, we integrated our dataset with the Allen Brain Atlas in situ data, publicly available adult hypothalamic scRNA-Seq dataset to understand hierarchy of hypothalamic cell differentiation, as well as re-defining cell types of the hypothalamus. We next used scRNA-Seq to phenotype multiple mutant lines, including a line that has been extensively characterised as a proof of concept (Ctnnb1 overexpression), and lines that have not been characterised (Nkx2.1, Nkx2.2, Dlx1/2 deletion). We show that this approach can rapidly and comprehensively characterize mutants that have altered hypothalamic patterning, and in doing so, have identified multiple genes that simultaneously repress posterior hypothalamic identity while promoting prethalamic identity. This result supports a modified columnar model of organization for the diencephalon, where prethalamus and hypothalamus are situated in adjacent dorsal and ventral domains of the anterior diencephalon. These data serve as a resource for further studies of hypothalamic development and dysfunction, and able to delineate transcriptional regulatory networks of hypothalamic formation. Lastly, using our mouse hypothalamus as a guideline, we are comparing dataset of developing chicken, zebrafish and human hypothalamus, to identify evolutionarily conserved and divergent region-specific gene regulatory networks. We aim to use this knowledge and information of key molecular pathways of human hypothalamic development and produce human hypothalamus organoids.

scholarly journals Molecular Logic of Hypothalamus Development

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A507-A507
Author(s):  
Thomas Kim
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Developmental Time ◽  
Specific Gene ◽  
Molecular Logic ◽  
Hypothalamic Nuclei ◽  
Physiological Homeostasis ◽  
Mutant Lines

Abstract The hypothalamus is a central regulator of physiological homeostasis. During development, multiple transcription factors coordinate the patterning and specification of hypothalamic nuclei. However, the molecular mechanisms controlling hypothalamic patterning and cell fate specification are poorly understood. To identify genes that control these processes, we have previously used single-cell RNA sequencing (scRNA-Seq) to profile mouse hypothalamic gene expression across multiple developmental time points and established database HyDD (Hypothalamus Developmental Database). We next used HyDD to characterize multiple mutant lines targetting key transcription factors that came out from our scRNA-Seq database (Nkx2.2, Dlx1/2, Isl1, Foxd1, Lhx2), and was able to comprehensively characterize mutants that have altered hypothalamic patterning. Our phenotype result supports a modified columnar model of organization for the diencephalon, where prethalamus and hypothalamus are situated in adjacent dorsal and ventral domains of the anterior diencephalon. Furthermore, using our mouse hypothalamus as a guideline, we are comparing scRNA-Seq dataset of developing chicken, zebrafish and human hypothalamus, to identify evolutionarily conserved and divergent region-specific gene regulatory networks. Lastly, we are improving mouse HyDD, in order to characterize adult hypothalamus neuronal subtypes.

scholarly journals Hyperactive WNT/CTNNB1 signaling induces a competing cell proliferation and epidermal differentiation response in the mouse mammary epithelium

2021 ◽  
Author(s):  
Larissa Mourao ◽  
Amber L. Zeeman ◽  
Katrin E. Wiese ◽  
Anika Bongaarts ◽  
Lieve L. Oudejans ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Fate ◽  
De Novo ◽  
Mammary Epithelium ◽  
Mechanistic Explanation ◽  
Tumor Formation ◽  
Epidermal Differentiation ◽  
Cell Proliferation And Differentiation ◽  
Primary Mouse ◽  
Proliferation And Differentiation

In the past forty years, the WNT/CTNNB1 signaling pathway has emerged as a key player in mammary gland development and homeostasis. While also evidently involved in breast cancer, much unclarity continues to surround its precise role in mammary tumor formation and progression. This is largely due to the fact that the specific and direct effects of hyperactive WNT/CTNNB1 signaling on the mammary epithelium remain unknown. Here we use a primary mouse mammary organoid culture system to close this fundamental knowledge gap. We show that hyperactive WNT/CTNNB1 signaling induces competing cell proliferation and differentiation responses. While proliferation is dominant at lower levels of WNT/CTNNB1 signaling activity, higher levels cause reprogramming towards an epidermal cell fate. We show that this involves de novo activation of the epidermal differentiation cluster (EDC) locus and we identify master regulatory transcription factors that likely control the process. This is the first time that the molecular and cellular dose-response effects of WNT/CTNNB1 signaling in the mammary epithelium have been dissected in such detail. Our analyses reveal that the mammary epithelium is exquisitely sensitive to small changes in WNT/CTNNB1 signaling and offer a mechanistic explanation for the squamous differentiation that is observed in some WNT/CTNNB1 driven tumors.

scholarly journals Integrating transcriptome and metabolome reveals molecular networks involved in genetic and environmental variation in tobacco

DNA Research ◽  
2020 ◽  
Vol 27 (2) ◽  
Author(s):  
Pingping Liu ◽  
Jie Luo ◽  
Qingxia Zheng ◽  
Qiansi Chen ◽  
Niu Zhai ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Developmental Stages ◽  
De Novo ◽  
Developmental Process ◽  
Pearson Correlation ◽  
Molecular Networks ◽  
Environmental Perturbations ◽  
Carotenoid Metabolism ◽  
Gene Modules

Abstract Tobacco (Nicotiana tabacum) is one of the most widely cultivated commercial non-food crops with significant social and economic impacts. Here we profiled transcriptome and metabolome from 54 tobacco samples (2–3 replicates; n = 151 in total) collected from three varieties (i.e. genetic factor), three locations (i.e. environmental factor), and six developmental stages (i.e. developmental process). We identified 3,405 differentially expressed (DE) genes (DEGs) and 371 DE metabolites, respectively. We used quantitative real-time PCR to validate 20 DEGs, and confirmed 18/20 (90%) DEGs between three locations and 16/20 (80%) with the same trend across developmental stages. We then constructed nine co-expression gene modules and four co-expression metabolite modules , and defined seven de novo regulatory networks, including nicotine- and carotenoid-related regulatory networks. A novel two-way Pearson correlation approach was further proposed to integrate co-expression gene and metabolite modules to identify joint gene–metabolite relations. Finally, we further integrated DE and network results to prioritize genes by its functional importance and identified a top-ranked novel gene, LOC107773232, as a potential regulator involved in the carotenoid metabolism pathway. Thus, the results and systems-biology approaches provide a new avenue to understand the molecular mechanisms underlying complex genetic and environmental perturbations in tobacco.

scholarly journals Insulin resistance and cancer: the role of insulin and IGFs

2012 ◽  
Vol 20 (1) ◽  
pp. R1-R17 ◽  
Author(s):  
Sefirin Djiogue ◽  
Armel Hervé Nwabo Kamdje ◽  
Lorella Vecchio ◽  
Maulilio John Kipanyula ◽  
Mohammed Farahna ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
Energy Metabolism ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Tumor Development ◽  
Epidemiological Studies ◽  
High Energy

Insulin, IGF1, and IGF2 are the most studied insulin-like peptides (ILPs). These are evolutionary conserved factors well known as key regulators of energy metabolism and growth, with crucial roles in insulin resistance-related metabolic disorders such as obesity, diseases like type 2 diabetes mellitus, as well as associated immune deregulations. A growing body of evidence suggests that insulin and IGF1 receptors mediate their effects on regulating cell proliferation, differentiation, apoptosis, glucose transport, and energy metabolism by signaling downstream through insulin receptor substrate molecules and thus play a pivotal role in cell fate determination. Despite the emerging evidence from epidemiological studies on the possible relationship between insulin resistance and cancer, our understanding on the cellular and molecular mechanisms that might account for this relationship remains incompletely understood. The involvement of IGFs in carcinogenesis is attributed to their role in linking high energy intake, increased cell proliferation, and suppression of apoptosis to cancer risks, which has been proposed as the key mechanism bridging insulin resistance and cancer. The present review summarizes and discusses evidence highlighting recent advances in our understanding on the role of ILPs as the link between insulin resistance and cancer and between immune deregulation and cancer in obesity, as well as those areas where there remains a paucity of data. It is anticipated that issues discussed in this paper will also recover new therapeutic targets that can assist in diagnostic screening and novel approaches to controlling tumor development.

scholarly journals Gene regulatory networks controlling differentiation, survival, and diversification of hypothalamic Lhx6-expressing GABAergic neurons

2020 ◽  
Author(s):  
Dong Won Kim ◽  
Kai Liu ◽  
Zoe Qianyi Wang ◽  
Yi Stephanie Zhang ◽  
Abhijith Bathini ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Gabaergic Neurons ◽  
Zona Incerta ◽  
Long Distance ◽  
Hypothalamic Neurons ◽  
Cortical Interneuron ◽  
Tangential Migration ◽  
Innate Behaviors

AbstractGABAergic neurons of the hypothalamus regulate many innate behaviors, but little is known about the mechanisms that control their development. We previously identified hypothalamic neurons that express the LIM homeodomain transcription factor Lhx6, a master regulator of cortical interneuron development, as sleep-promoting. In contrast to telencephalic interneurons, hypothalamic Lhx6 neurons do not undergo long-distance tangential migration and do not express cortical interneuronal markers such as Pvalb. Here, we show that Lhx6 is necessary for the survival of hypothalamic neurons. Dlx1/2, Nkx2-2, and Nkx2-1 are each required for specification of spatially distinct subsets of hypothalamic Lhx6 neurons, and that Nkx2-2+/Lhx6+ neurons of the zona incerta are responsive to sleep pressure. We further identify multiple neuropeptides that are enriched in spatially segregated subsets of hypothalamic Lhx6 neurons, and that are distinct from those seen in cortical neurons. These findings identify common and divergent molecular mechanisms by which Lhx6 controls the development of GABAergic neurons in the hypothalamus.

scholarly journals Engineering Cell Fate: The Roles of iPSC Transcription Factors, Chemicals, Barriers and Enhancing Factors in Reprogramming and Transdifferentiation

2015 ◽  
Author(s):  
Behnam Ebrahimi
Keyword(s):  
Cell Fate ◽  
Regulatory Networks ◽  
Viral Vectors ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Direct Reprogramming ◽  
Comprehensive Overview ◽  
Ips Cell ◽  
Chemical Reprogramming

Direct reprogramming technology has emerged as an outstanding technique for the generation of induced pluripotent stem (iPS) cells and various specialized cells directly from somatic cells of different species. Recent studies dissecting the molecular mechanisms of reprogramming have methodologically improved the quality, ease and efficiency of reprogramming and eliminated the need for genome modifications with integrating viral vectors. With these advancements, direct reprogramming technology has moved closer to clinical application. Here, we provide a comprehensive overview of the cutting-edge findings regarding distinct barriers of reprogramming to pluripotency, strategies to enhance reprogramming efficiency, and chemical reprogramming as one of the non-integrating approaches in iPS cell generation. In addition to direct transdifferentiation, pluripotency factor-induced transdifferentiation or cell activation and signaling directed (CASD) lineage conversion is described as a robust strategy for the generation of both tissue-specific progenitors and clinically relevant cell types. Then, we consider the possibility that a combined method of inhibition of roadblocks (e.g. p53, p21, p57, Mbd3, etc.), and application of enhancing factors in a chemical reprogramming paradigm would be a safe, reliable and effective approach in pluripotent reprogramming and transdifferentiation. Furthermore, with respect to the state of native, aberrant, and target gene regulatory networks in reprogrammed cell populations, CellNet is reviewed as a computational platform capable of evaluating the fidelity of reprogramming methods and refining current engineering strategies. Ultimately, we conclude that a faithful, highly efficient and integration-free reprogramming paradigm would provide powerful tools for research studies, drug-based induced regeneration, cell transplantation therapies and other regenerative medicine purposes.

scholarly journals Single cell transcriptomic analysis of human pluripotent stem cell chondrogenesis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chia-Lung Wu ◽  
Amanda Dicks ◽  
Nancy Steward ◽  
Ruhang Tang ◽  
Dakota B. Katz ◽  
...  
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Cell Fate ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Cartilage Regeneration ◽  
Target Cells ◽  
Neural Cells ◽  
Fate Decision ◽  
Induced Pluripotent

AbstractThe therapeutic application of human induced pluripotent stem cells (hiPSCs) for cartilage regeneration is largely hindered by the low yield of chondrocytes accompanied by unpredictable and heterogeneous off-target differentiation of cells during chondrogenesis. Here, we combine bulk RNA sequencing, single cell RNA sequencing, and bioinformatic analyses, including weighted gene co-expression analysis (WGCNA), to investigate the gene regulatory networks regulating hiPSC differentiation under chondrogenic conditions. We identify specific WNTs and MITF as hub genes governing the generation of off-target differentiation into neural cells and melanocytes during hiPSC chondrogenesis. With heterocellular signaling models, we further show that WNT signaling produced by off-target cells is responsible for inducing chondrocyte hypertrophy. By targeting WNTs and MITF, we eliminate these cell lineages, significantly enhancing the yield and homogeneity of hiPSC-derived chondrocytes. Collectively, our findings identify the trajectories and molecular mechanisms governing cell fate decision in hiPSC chondrogenesis, as well as dynamic transcriptome profiles orchestrating chondrocyte proliferation and differentiation.

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