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![Oriented cell division in the C. elegans zygote. The first zygotic division in C. elegans proceeds asymmetrically to generate differential AB and P1 cells. Par proteins in the zygote are polarized along an anterior-posterior cortical axis: the anteriorally-localized Par-3/Par-6/aPKC (red) and posteriorally-localized Par-1/Par-2 (blue) complexes mutually repress cortical localization of one another. Spindle orientation along this polarity axis is regulated by the GPR-1/2 and LIN-5 complex (which is enriched at the posterior cortex), ensuring proper asymmetry in polarity protein distribution in daughter cells. This complex also induces a physical, posterior displacement of the spindle apparatus relative to the cell center, thereby generating a size asymmetry in offspring. Spindles in the resulting AB and P1 cells rotate relative to the original zygotic axis in subsequent divisions, yielding further diversification at the four-cell stage. These cells ultimately lead to the production of distinct cell lineages and their associated tissue structures in the developing animal [11].](publication/287334140/figure/fig1/AS:614084382822416@1523420534935/Oriented-cell-division-in-the-C-elegans-zygote-The-first-zygotic-division-in-C-elegans.png)
Oriented cell division in the C. elegans zygote. The first zygotic division in C. elegans proceeds asymmetrically to generate differential AB and P1 cells. Par proteins in the zygote are polarized along an anterior-posterior cortical axis: the anteriorally-localized Par-3/Par-6/aPKC (red) and posteriorally-localized Par-1/Par-2 (blue) complexes mutually repress cortical localization of one another. Spindle orientation along this polarity axis is regulated by the GPR-1/2 and LIN-5 complex (which is enriched at the posterior cortex), ensuring proper asymmetry in polarity protein distribution in daughter cells. This complex also induces a physical, posterior displacement of the spindle apparatus relative to the cell center, thereby generating a size asymmetry in offspring. Spindles in the resulting AB and P1 cells rotate relative to the original zygotic axis in subsequent divisions, yielding further diversification at the four-cell stage. These cells ultimately lead to the production of distinct cell lineages and their associated tissue structures in the developing animal [11].
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The ability to dictate cell fate decisions is critical during animal development. Moreover, faithful execution of this process ensures proper tissue homeostasis throughout adulthood, whereas defects in the molecular machinery involved may contribute to disease. Evolutionarily conserved protein complexes control cell fate decisions across diverse ti...
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... studies in model organisms demonstrated that aPKC activity was critical for regulation of cortical polarity. In the C. elegans zygote, the Par complex was found to promote polarity along the anterior-posterior (A-P) axis in the zygote [3][4][5] (Figure 1). Upon fertilization, a breaking of symmetry initiates a "cortical flow" using contractile actomyosin forces to mediate movement of the anterior Par genes (aPKC/Par-3/Par-6) to the anterior side of the cell [4,5]. The posterior Par genes (Par-1/Par-2/Lgl [lethal giant larvae]) are initially present on the posterior side but expand along the posterior cortex with the help of Par-2 phospholipid binding activity, as well as positive feedback through membrane recruitment of cytoplasmic Par-2 by membrane bound Par-2 [6,7]. Once polarity has been established, phosphorylation by members of both the anterior and posterior Par genes function to maintain a mutually exclusive A-P boundary [6,8] (Figure 1). The serine/threonine kinase Par-1 functions to restrict the anterior members via phosphorylation of Par-3, while the kinase activity of aPKC functions to restrict anterior members via phosphorylation of Par-2 and Lgl [8][9][10]. Polarization of the embryo functions to produce distinct cell types by segregation of cell fate determinants upon oriented divisions [11] (Figure 1). Allotment of these determinants codifies the body structure of the mature animal, with many determinants functioning as cell cycle regulators, transcription factors, and components of cell trafficking complexes to achieve and maintain the final body pattern (for a more extended review of these functions see [12]). Without proper polarity, restriction of cell fate determinants and thus development of the animal are compromised. In embryos that are deficient of myosin, Par-6 distribution to the anterior cortex is compromised, indicating a requirement of cortical flow [5]. The Par genes themselves are also required for cortical flow, as embryos lacking Par-3 and Par-6 are deficient in this activity [3][4][5]. The first zygotic division in C. elegans proceeds asymmetrically to generate differential AB and P1 cells. Par proteins in the zygote are polarized along an anterior-posterior cortical axis: the anteriorally-localized Par-3/Par-6/aPKC (red) and posteriorally-localized Par-1/Par-2 (blue) complexes mutually repress cortical localization of one another. Spindle orientation along this polarity axis is regulated by the GPR-1/2 and LIN-5 complex (which is enriched at the posterior cortex), ensuring proper asymmetry in polarity protein distribution in daughter cells. This complex also induces a physical, posterior displacement of the spindle apparatus relative to the cell center, thereby generating a size asymmetry in offspring. Spindles in the resulting AB and P1 cells rotate relative to the original zygotic axis in subsequent divisions, yielding further diversification at the four-cell stage. These cells ultimately lead to the production of distinct cell lineages and their associated tissue structures in the developing animal ...
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... studies in model organisms demonstrated that aPKC activity was critical for regulation of cortical polarity. In the C. elegans zygote, the Par complex was found to promote polarity along the anterior-posterior (A-P) axis in the zygote [3][4][5] (Figure 1). Upon fertilization, a breaking of symmetry initiates a "cortical flow" using contractile actomyosin forces to mediate movement of the anterior Par genes (aPKC/Par-3/Par-6) to the anterior side of the cell [4,5]. The posterior Par genes (Par-1/Par-2/Lgl [lethal giant larvae]) are initially present on the posterior side but expand along the posterior cortex with the help of Par-2 phospholipid binding activity, as well as positive feedback through membrane recruitment of cytoplasmic Par-2 by membrane bound Par-2 [6,7]. Once polarity has been established, phosphorylation by members of both the anterior and posterior Par genes function to maintain a mutually exclusive A-P boundary [6,8] (Figure 1). The serine/threonine kinase Par-1 functions to restrict the anterior members via phosphorylation of Par-3, while the kinase activity of aPKC functions to restrict anterior members via phosphorylation of Par-2 and Lgl [8][9][10]. Polarization of the embryo functions to produce distinct cell types by segregation of cell fate determinants upon oriented divisions [11] (Figure 1). Allotment of these determinants codifies the body structure of the mature animal, with many determinants functioning as cell cycle regulators, transcription factors, and components of cell trafficking complexes to achieve and maintain the final body pattern (for a more extended review of these functions see [12]). Without proper polarity, restriction of cell fate determinants and thus development of the animal are compromised. In embryos that are deficient of myosin, Par-6 distribution to the anterior cortex is compromised, indicating a requirement of cortical flow [5]. The Par genes themselves are also required for cortical flow, as embryos lacking Par-3 and Par-6 are deficient in this activity [3][4][5]. The first zygotic division in C. elegans proceeds asymmetrically to generate differential AB and P1 cells. Par proteins in the zygote are polarized along an anterior-posterior cortical axis: the anteriorally-localized Par-3/Par-6/aPKC (red) and posteriorally-localized Par-1/Par-2 (blue) complexes mutually repress cortical localization of one another. Spindle orientation along this polarity axis is regulated by the GPR-1/2 and LIN-5 complex (which is enriched at the posterior cortex), ensuring proper asymmetry in polarity protein distribution in daughter cells. This complex also induces a physical, posterior displacement of the spindle apparatus relative to the cell center, thereby generating a size asymmetry in offspring. Spindles in the resulting AB and P1 cells rotate relative to the original zygotic axis in subsequent divisions, yielding further diversification at the four-cell stage. These cells ultimately lead to the production of distinct cell lineages and their associated tissue structures in the developing animal ...
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... studies in model organisms demonstrated that aPKC activity was critical for regulation of cortical polarity. In the C. elegans zygote, the Par complex was found to promote polarity along the anterior-posterior (A-P) axis in the zygote [3][4][5] (Figure 1). Upon fertilization, a breaking of symmetry initiates a "cortical flow" using contractile actomyosin forces to mediate movement of the anterior Par genes (aPKC/Par-3/Par-6) to the anterior side of the cell [4,5]. The posterior Par genes (Par-1/Par-2/Lgl [lethal giant larvae]) are initially present on the posterior side but expand along the posterior cortex with the help of Par-2 phospholipid binding activity, as well as positive feedback through membrane recruitment of cytoplasmic Par-2 by membrane bound Par-2 [6,7]. Once polarity has been established, phosphorylation by members of both the anterior and posterior Par genes function to maintain a mutually exclusive A-P boundary [6,8] (Figure 1). The serine/threonine kinase Par-1 functions to restrict the anterior members via phosphorylation of Par-3, while the kinase activity of aPKC functions to restrict anterior members via phosphorylation of Par-2 and Lgl [8][9][10]. Polarization of the embryo functions to produce distinct cell types by segregation of cell fate determinants upon oriented divisions [11] (Figure 1). Allotment of these determinants codifies the body structure of the mature animal, with many determinants functioning as cell cycle regulators, transcription factors, and components of cell trafficking complexes to achieve and maintain the final body pattern (for a more extended review of these functions see [12]). Without proper polarity, restriction of cell fate determinants and thus development of the animal are compromised. In embryos that are deficient of myosin, Par-6 distribution to the anterior cortex is compromised, indicating a requirement of cortical flow [5]. The Par genes themselves are also required for cortical flow, as embryos lacking Par-3 and Par-6 are deficient in this activity [3][4][5]. The first zygotic division in C. elegans proceeds asymmetrically to generate differential AB and P1 cells. Par proteins in the zygote are polarized along an anterior-posterior cortical axis: the anteriorally-localized Par-3/Par-6/aPKC (red) and posteriorally-localized Par-1/Par-2 (blue) complexes mutually repress cortical localization of one another. Spindle orientation along this polarity axis is regulated by the GPR-1/2 and LIN-5 complex (which is enriched at the posterior cortex), ensuring proper asymmetry in polarity protein distribution in daughter cells. This complex also induces a physical, posterior displacement of the spindle apparatus relative to the cell center, thereby generating a size asymmetry in offspring. Spindles in the resulting AB and P1 cells rotate relative to the original zygotic axis in subsequent divisions, yielding further diversification at the four-cell stage. These cells ultimately lead to the production of distinct cell lineages and their associated tissue structures in the developing animal ...
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... molecular machinery through which Pins directs spindle positioning has been elegantly illuminated over the past decade. Pins activity relies on its ability to organize microtubule-associated motor proteins that influence the dynamics of the mitotic spindle [60]. Initial studies demonstrated a role for the minus-end directed motor cytoplasmic dynein downstream of Pins. Together with the Dynactin complex [77,78], Dynein exerts cortical pulling forces on spindle microtubules that are critical not only for precise alignment with Pins [79][80][81], but in systems such as the C. elegans zygote this unequal cortical force also physically displaces the spindle along the polarity axis to induce daughter cell size asymmetry [71,72] (Figure 1). Studies in cell culture have nicely demonstrated that cortical Dynein is likely sufficient for the force generation aspect of Pins function [82]. Pins association with the dynactin/dynein complex is indirect, relying on a key adaptor protein called Mushroom body defect (Mud), as well as possible other unknown components. Pins and Mud directly interact, and Pins is required for cortical Mud localization, which, in turn, is necessary for subsequent dynein activation [79,81]. Loss of Pins, Mud, or dynactin/dynein all perturb proper spindle orientation. Elegant fate tracking experiments in Drosophila neuroblasts have demonstrated that loss of spindle orientation alone (through loss of Mud expression) can result in improper cell fate specification, specifically by expanding the stem cell pool [83]. Furthermore, loss of Pins is synthetic with loss of the polarity gene Lethal(2) giant larvae (Lgl) in Drosophila neuroblasts leading to massive stem cell overgrowth and brain tumors with invasive capabilities upon implantation in wild-type host flies [14]. These studies illustrate the importance of Pins/Mud-mediated spindle orientation in cell fate acquisition and may suggest a tumor suppressor activity in stem cells [84]. studies identified a role for a second pathway downstream of Pins during spindle positioning. Again using Drosophila neuroblasts as a model, Siegrist and Doe identified a role for the tumor suppressor protein Discs large (Dlg) [85] (Figure 4A). Dlg directly binds Pins but only after Pins has been phosphorylated by the mitotic kinase Aurora-A, highlighting a temporal link with cell cycle progression [80,86]. Pins/Dlg association has subsequently been shown to be important for spindle positioning in Drosophila epithelia and chick neuroepithelium [87,88]. Association with Dlg is necessary for subsequent binding and activation of a second microtubule motor, the plus-end directed kinesin Khc73 [85,89]. The function of this Dlg/Khc73 complex is two-fold. First, plus-end trafficking serves as a mode of microtubule-induced Pins polarity establishment [85]. Secondly, microtubule association of polarized Pins/Dlg/Khc73 serves as a capture site for dynamic astral microtubules that appears to initiate the spindle orientation process [80]. Subsequent Pins/Mud/Dynein-mediated forces complete the alignment process, resulting in synergistic function of the two motor-based pathways. Interestingly, a recent study demonstrated further collaboration between these Pins pathways in which Dynein and Khc73 are physically linked by a NudE/14-3-3 complex [90]. Thus, Pins permits accurate spindle orientation through a complex assembly of dual acting microtubule motors that cooperate to achieve maximum ...
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... cortical polarity has been established, the ability to reliably segregate polarized cell fate determinants differentially into respective daughter cells is mandated if asymmetric fate specification is to be achieved. Asymmetric fate inheritance occurs pursuant to a cleavage furrow ingression site that results in cytokinesis perpendicular to the polarity axis (Figures 1-3). Because the mitotic spindle equator marks the site of contractile ring formation [58], proper spindle alignment along the polarity axis plays an important role in cell fate specification. Several recent reviews have thoroughly detailed an impressively diverse set of spindle positioning pathways and the pathways through which they communicate with the spindle apparatus [59][60][61][62][63]. For brevity, we will restrict our discussion to two well-defined spindle orientation complexes, both of which have intricate links to cortical polarity systems that control cell fate specification. . Planar symmetric divisions yield two RG cells, whereas asymmetric divisions drive differentiation within the subventricular zone (SVZ) and cortex. These asymmetric divisions are associated with altered spindle orientation relative to the overlying epithelium and produce outer RG (oRG), basal progenitors (BP), or neuron cells; (B) The mouse epidermis also relies on balanced output in mitotic symmetry for development of several differentiated layers. Keratinocyte stem cells in the basal layer undergo symmetric divisions in order to promote tissue growth and expansion. Insc expression induces an apical-basal orientation of cell division that allows for differentiation necessary for tissue stratification. The LGN/NuMA complex is critical for maintaining proper spindle orientation during this ...
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... the most well-characterized spindle orientation complex is that assembled through the cortically-localized scaffold protein Partner of Inscuteable (Pins) ( Figure 4A). Drosophila Pins has evolutionarily conserved orthologs in worms (GPR1/2) and mammals (LGN) that, moreover, serve orthologous functions as spindle orientation regulators [64]. Cortical localization of Pins is dependent upon Inscuteable (Insc), a protein that also associates with the Par polarity complex [65,66]. Interestingly, Insc-mediated localization of Pins can be induced at specific developmental time points in order to signal a shift to asymmetric cell divisions. For example, in the neuroepithelium of the Drosophila optic lobe, expression of Insc induces apical Pins polarity and is associated with a switch to asymmetric divisions that yield a delaminated daughter cell that adopts a neuroblast fate [67]. A similar scenario occurs in the mouse epidermis in which Insc-mediated Pins polarization induces a switch from symmetrically dividing keratinocytes to asymmetric divisions critical for tissue stratification ( Figure 3B). Loss of Pins in these cells prevents fate transition, leading to underdeveloped skin tissue defective in proper fluid and electrolyte maintenance [68]. Pins-mediated spindle orientation is also influential in asymmetric division of Drosophila neural stem cells and mechanosensory hair cells [65,69,70] (Figure 2), the first zygotic division of developing C. elegans [71][72][73] (Figure 1), and mammalian cerebral neurogenesis controlled by oriented division of progenitor cells [74][75][76] (Figure 3A). Thus, Pins regulates spindle positioning within diverse cells and across evolutionary ...
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... not as extensively studied as the Pins complex, details of the molecular basis for Dsh-mediated spindle orientation have continued to emerge. An intriguing recent study found that deubiquitination of cortical Dsh by cylindromatosis (CYLD) contributed to its association with NuMA and the dynein/dynactin complex [112]. CYLD also stabilizes astral microtubules of the mitotic spindle, which further promotes activity with the cortical Dsh/NuMA during spindle positioning. These findings highlight a role for an additional post-translational modification in spindle positioning, together with the more appreciated role of phosphorylation discussed previously. Another recent study in C. elegans investigated the role of cell contacts in Dsh function. In the ABar and EMS cell divisions (see Figure 1), mitotic spindles reorient relative to the zygotic division in response to Wnt signaling through cortically enriched Dsh. Dejima et al. found that syndecan (SDN-1), a member of the heparin sulfate proteoglycan family, was responsible for the asymmetric localization of Dsh at the interface between these cells. SDN-1 was specifically required for spindle orientation in the ABar cell [113]. These recent findings collectively extend our understanding of how polarized Wnt signaling can communicate with spindle microtubules during oriented cell ...
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... Different proteins, cell fate determinants or complexes are involved in this process. First of all, cell polarity is established by the formation of the PAR complex at the apical side of the cell, unequal orientation of this complex regulates daughter MuSC fate (Dewey, Taylor, & Johnston, 2015) (Fig. 3). The PAR complex is composed of Partitioning defective protein 6 (= Pard6, Par6 in Drosophilia melanogaster), Partitioning defective protein 3 (= Pard3, Baz in Drosophilia melanogaster) and atypical protein kinase C (aPKC). ...
Skeletal muscle is a highly represented tissue in mammals and is composed of fibers that
are extremely adaptable and capable of regeneration. This characteristic of muscle fibers
is made possible by a cell type called satellite cells. Adjacent to the fibers, satellite cells
are found in a quiescent state and located between the muscle fibers membrane and
the basal lamina. These cells are required for the growth and regeneration of skeletal
muscle through myogenesis. This process is known to be tightly sequenced from the
activation to the differentiation/fusion of myofibers. However, for the past fifteen years,researchers have been interested in examining satellite cell heterogeneity and have
identified different subpopulations displaying distinct characteristics based on localization,
quiescence state, stemness capacity, cell-cycle progression or gene expression.
A small subset of satellite cells appears to represent multipotent long-term self-renewing
muscle stem cells (MuSC). All these distinctions led us to the hypothesis that the
characteristics of myogenesis might not be linear and therefore may be more permissive
based on the evidence that satellite cells are a heterogeneous population. In this review,
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... Asymmetric cell division (ACD) is a conserved mode of stem cell division that produces non-identical daughter cells essential for the generation of cell diversity throughout development [90,91]. ACD requires two critical processes, i.e., cell polarity and mitotic spindle orientation, to be coupled in a manner that leads to the unequal segregation of cell fate determinants. ...
A properly organized subcellular composition is essential to cell function. The canonical organizing principle within eukaryotic cells involves membrane-bound organelles; yet, such structures do not fully explain cellular complexity. Furthermore, discrete non-membrane-bound structures have been known for over a century. Liquid–liquid phase separation (LLPS) has emerged as a ubiquitous mode of cellular organization without the need for formal lipid membranes, with an ever-expanding and diverse list of cellular functions that appear to be regulated by this process. In comparison to traditional organelles, LLPS can occur across wider spatial and temporal scales and involves more distinct protein and RNA complexes. In this review, we discuss the impacts of LLPS on the organization of stem cells and their function during development. Specifically, the roles of LLPS in developmental signaling pathways, chromatin organization, and gene expression will be detailed, as well as its impacts on essential processes of asymmetric cell division. We will also discuss how the dynamic and regulated nature of LLPS may afford stem cells an adaptable mode of organization throughout the developmental time to control cell fate. Finally, we will discuss how aberrant LLPS in these processes may contribute to developmental defects and disease.
... Distinct cell fate acquisition is achieved through asymmetric cell division (ACD), which generates two molecularly non-identical progeny cells (e.g., one self-renewing stem cell and one differentiating progenitor cell). Across diverse stem cell types, ACD is orchestrated through two intersecting processes, cortical polarity and mitotic spindle orientation, the core components of which have been shown to be evolutionarily conserved (Dewey et al., 2015a). Neural stems cells (neuroblasts; NBs) in the developing Drosophila central nervous system are a wellstudied and proven model system for studying the molecular mechanisms underpinning these core ACD events (Homem and Knoblich, 2012). ...
... Second, Pins binds Mushroom body defect (Mud) to generate spindle forces via the Dynein motor complex (Bowman et al., 2006;Siller et al., 2006). The Pins/Mud complex has been particularly well-studied in diverse cell types across taxa (Dewey et al., 2015a;di Pietro et al., 2016), yet key knowledge gaps remain in our understanding of its molecular functions. Perhaps most notably, the ability of Pins to directly bind Mud is mutually exclusive with its interaction with Inscuteable (Insc), an adaptor protein that is also apically polarized in NBs (Culurgioni et al., 2011;Zhu et al., 2011;Mauser and Prehoda, 2012). ...
Asymmetric cell division (ACD) allows stem cells to generate differentiating progeny while simultaneously maintaining their own pluripotent state. ACD involves coupling mitotic spindle orientation with cortical polarity cues to direct unequal segregation of cell fate determinants. In Drosophila neural stem cells (neuroblasts; NBs), spindles orient along an apical-basal polarity axis through a conserved complex of Partner of Inscuteable (Pins; human LGN) and Mushroom body defect (Mud; human NuMA). While many details of its function are well known, the molecular mechanics that drive assembly of the cortical Pins/Mud complex remain unclear, particularly with respect to the mutually exclusive Pins complex formed with the apical scaffold protein Inscuteable (Insc). Here we identify Hu li tai shao (Hts; human Adducin) as a direct Mud-binding protein, using an aldolase fold within its head domain (HtsHEAD) to bind a short Mud coiled-coil domain (MudCC) that is adjacent to the Pins-binding domain (MudPBD). Hts is expressed throughout the larval central brain and apically polarizes in mitotic NBs where it is required for Mud-dependent spindle orientation. In vitro analyses reveal that Pins undergoes liquid-liquid phase separation with Mud, but not with Insc, suggesting a potential molecular basis for differential assembly mechanics between these two competing apical protein complexes. Furthermore, we find that Hts binds an intact Pins/Mud complex, reduces the concentration threshold for its phase separation, and alters the liquid-like property of the resulting phase separated droplets. Domain mapping and mutational analyses implicate critical roles for both multivalent interactions (via MudCC oligomerization) and protein disorder (via an intrinsically disordered region in Hts; HtsIDR) in phase separation of the Hts/Mud/Pins complex. Our study identifies a new component of the spindle positioning machinery in NBs and suggests that phase separation of specific protein complexes might regulate ordered assembly within the apical domain to ensure proper signaling output.
... The absence of dystrophin impairs muscle regeneration by disrupting the asymmetric division of MuSCs. In general, cell cortex polarization and specific mitotic spindle orientation are determinants for asymmetric cell division [33]. Dystrophin in the sarcolemma interacts with cell polarity-regulating serine/threonine-protein kinase MARK2 and is highly expressed in MuSCs that are about to undergo cell division, suggesting that dystrophin is essential to regulate cell polarity and asymmetric division of MuSCs [30,34]. ...
Duchenne muscular dystrophy (DMD) is a severe, progressive, muscle-wasting disease, characterized by progressive deterioration of skeletal muscle that causes rapid loss of mobility. The failure in respiratory and cardiac muscles is the underlying cause of premature death in most patients with DMD. Mutations in the gene encoding dystrophin result in dystrophin deficiency, which is the underlying pathogenesis of DMD. Dystrophin-deficient myocytes are dysfunctional and vulnerable to injury, triggering a series of subsequent pathological changes. In this review, we detail the molecular mechanism of DMD, dystrophin deficiency-induced muscle cell damage (oxidative stress injury, dysregulated calcium homeostasis, and sarcolemma instability) and other cell damage and dysfunction (neuromuscular junction impairment and abnormal differentiation of muscle satellite). We also describe aberrant function of other cells and impaired muscle regeneration due to deterioration of the muscle microenvironment, and dystrophin deficiency-induced multiple organ dysfunction, while summarizing the recent advances in the treatment of DMD.
... Spindle orientation provides a functional link between spatial context and fate of the progeny of a cell division in many contexts. For instance, spindle orientation influences the position, the size and the fate of the two daughter cells of an epithelial division, impacting upon cell diversification and tissue homeostasis and morphogenesis (Bergstralh et al., 2017;Dewey et al., 2015;di Pietro et al., 2016;Lu and Johnston, 2013;Seldin and Macara, 2017). Errors in the control of orientation of the mitotic spindle lead to developmental defects and cancer (Bergstralh and St Johnston, 2014;Lechler and Mapelli, 2021;Lu and Johnston, 2013). ...
The fate of the two daughter cells is intimately connected to their positioning, which is in turn regulated by cell junction remodelling and orientation of the mitotic spindle. How multiple cues are integrated to dictate the ultimate positioning of daughters is not clear. Here, we identify novel mechanisms of regulation of daughter positioning in single MCF10A cells. The polarity protein, Scribble cooperates with E-cadherin for sequential roles in daughter positioning. First Scribble stabilises E-cadherin at the mitotic cortex as well as the retraction fibres, to mediate spindle orientation. Second, Scribble re-locates to the junction between the two daughters to allow a new E-cadherin-based-interface to form between them, influencing the width of the nascent daughter–daughter junction and subsequent cell positioning. Thus, E-cadherin and Scribble dynamically relocate to different intracellular sites during cell division to orient the mitotic spindle and control placement of the daughter cells after cell division.
This article has an associated First Person interview with the first author of the paper.
... The ICM cells subsequently localize to one pole of the forming blastocyst, engendering a topological asymmetry that orients the further formation of the embryo (Figure 2A). A multitude of signaling factors, including morphogens forming concentration gradients for patterning and transcriptional regulators, have been identified to orchestrate subsequent oriented cell divisions (Dewey et al., 2015) and cell fate choices (Gerri et al., 2020;Shahbazi, 2020) with an increasing appreciation of the mechanical forces at play (Valet et al., 2021). Waddington's landscape with the marble representing a cell to take on a set of alternative developmental paths, with the three basins at the base of the hill, representing the alternative differentiated cell fates (left). ...
... Perspective Further, we note that the most predictive feature set may (and does) vary piecewise in time. For example, geometry and morphogens play an important role in early embryogenesis, whereas their role may be rather marginal in fully structured organ systems, which, however, continue to integrate environmental signals (Dewey et al., 2015). Therefore, building local prediction models is necessary and compatible with short-term predictability if one assumes a chaotic model of cell differentiation and fate decisions. ...
The concept of cell fate relates to the future identity of a cell, and its daughters, which is obtained via cell differentiation and division. Understanding, predicting, and manipulating cell fate has been a long-sought goal of developmental and regenerative biology. Recent insights obtained from single-cell genomic and integrative lineage-tracing approaches have further aided to identify molecular features predictive of cell fate. In this perspective, we discuss these approaches with a focus on theoretical concepts and future directions of the field to dissect molecular mechanisms underlying cell fate.
... However, cell fate decisions refer to the cell differentiation in a specific direction due to the constraints of internal or external conditions, which determine cell fates of future development [3,4]. Correct execution of cell fates ensures normal development of entire tissues, and defects in related molecular mechanisms may lead to disease [5]. Cell fate decisions play crucial roles in causing cancer, tumor migration and transplantation, and gene therapy etc. ...
... Biological cell fate decisions are closely related to cancer, tumor migration and certain diseases [5][6][7][8][9][10]. These cell fate decision processes are usually strictly controlled by various regulators [11]. ...
Cell fate decision processes are regulated by networks which contain different molecules and interactions. Different network topologies may exhibit synergistic or antagonistic effects on cellular functions. Here, we analyze six most common small networks with regulatory logic AND or OR, trying to clarify the relationship between network topologies and synergism (or antagonism) related to cell fate decisions. We systematically examine the contribution of both network topologies and regulatory logic to the cell fate synergism by bifurcation and combinatorial perturbation analysis. Initially, under a single set of parameters, the synergism of three types of networks with AND and OR logic is compared. Furthermore, to consider whether these results depend on the choices of parameter values, statistics on the synergism of five hundred parameter sets is performed. It is shown that the results are not sensitive to parameter variations, indicating that the synergy or antagonism mainly depends on the network topologies rather than the choices of parameter values. The results indicate that the topology with “Dual Inhibition” shows good synergism, while the topology with “Dual Promotion” or “Hybrid” shows antagonism. The results presented here may help us to design synergistic networks based on network structure and regulation combinations, which has promising implications for cell fate decisions and drug combinations.
... ACD is a mechanism for cell-type diversification seen in numerous species, including yeast, plants, and animal cells because it results in the formation of two daughter cells with distinct fates 14,15 . The process can be divided into four steps: i) acquisition of a polarity axis by the mother cell, ii) redistribution of cell fate determinants with respect to this polarity axis; iii) lining up the mitotic spindle with the cell polarity axis, and iv) asymmetric segregation of cell determinants at cytokinesis inducing different cell fates in each daughter cell. ...
The coordination between cell proliferation and cell polarity is crucial to orient the asymmetric cell divisions to generate cell diversity in epithelia. In many instances, the Frizzled/Dishevelled planar cell polarity pathway is involved in mitotic spindle orientation, but how this is spatially and temporally coordinated with cell cycle progression has remained elusive. Using Drosophila sensory organ precursor cells as a model system, we show that Cyclin A, the main Cyclin driving the transition to M-phase of the cell cycle, is recruited to the apical-posterior cortex in prophase by the Frizzled/Dishevelled complex. This cortically localized Cyclin A then regulates the orientation of the division by recruiting Mud, a homologue of NuMA, the well-known spindle-associated protein. The observed non-canonical subcellular localization of Cyclin A reveals this mitotic factor as a direct link between cell proliferation, cell polarity and spindle orientation. The Frizzled/Dishevelled planar cell polarity pathway is involved in mitotic spindle orientation, but how this is coordinated with the cell cycle is unclear. Here, the authors show with Drosophila sensory organ precursor cells that Cyclin A is recruited in prophase by Frizzled/Dishevelled, regulating division orientation.
... Here, we define "cell division orientation" as a combination of cell volume segregation direction and ratio during cytokinesis, which is mainly regulated by cell polarization [15,59], experiment are obtained from 222 wild-type embryos in a previous dataset [2]. The intercept is predetermined as −Δt 0 = −2.2784 ...
Morphogenesis is a precise and robust dynamic process during metazoan embryogenesis, consisting of both cell proliferation and cell migration. Despite the fact that much is known about specific regulations at molecular level, how cell proliferation and migration together drive the morphogenesis at cellular and organismic levels is not well understood. Using Caenorhabditis elegans as the model animal, we present a phase field model to compute early embryonic morphogenesis within a confined eggshell. With physical information about cell division obtained from three-dimensional time-lapse cellular imaging experiments, the model can precisely reproduce the early morphogenesis process as seen in vivo , including time evolution of location and morphology of each cell. Furthermore, the model can be used to reveal key cell-cell attractions critical to the development of C . elegans embryo. Our work demonstrates how genetic programming and physical forces collaborate to drive morphogenesis and provides a predictive model to decipher the underlying mechanism.
... The orientation of cell division plays a key role in development, morphogenesis, organogenesis, differentiation, and functions from a single-cell zygote to adult tissues (Castanon and González-Gaitán 2011;Yang et al. 2015). Symmetric or asymmetric cell division and equal or unequal distribution of cell compartments between cells derived from mitosis also determine the fate of the resulting daughter cells (Neumüller and Knoblich 2009;Dewey et al. 2015). Components of the planar polarity protein (PCP) have been shown to be expressed in the progenitors of the pancreas that line the ducts during embryogenesis of the pancreas (Cortijo et al. 2012). ...
Conventional methods for obtaining pancreatic β cells are based on simulating the embryonic development phase of endocrine cells via hierarchical differentiation of pluripotent stem cells (PSCs). Accordingly, we attempted to modify the protocols for obtaining insulin-secreting cells (ISCs) by sequential differentiation of a human embryonic stem cell (hESC), using the HS181 cell line. Furthermore, we hypothesize that actual pancreatic endocrine cells may arise from trans-differentiation of mature ductal cells after the embryonic developmental stage and throughout the rest of life. According to the hypothesis, ductal cells are trans-differentiated into endocrine and exocrine cells, undergoing a partial epithelial to mesenchymal transition (EMT). To address this issue, we developed two new protocols based on hESC differentiation to obtain ductal cells and then induce EMT in cells to obtain hormone-secreting islet-like cells (HSCs). The ductal (pre-EMT exocrine) cells were then induced to undergo partial EMT by treating with Wnt3a and activin A, in hypoxia. The cell derived from the latter method significantly expressed the main endocrine cell–specific markers and also β cells, in particular. These experiments not only support our hypothetical model but also offer a promising approach to develop new methods to compensate β cell depletion in patients with type 1 diabetes mellitus (T1DM). Although this protocol of generating islet-like cells from ductal cells has a potential to treat T1DM, this strategy may be exploited to optimize the function of these cells in an animal model and future clinical applications.
