what happens to the extruded nucleus of a developing rbc

Introduction

Mature red claret cells (RBCs) result from a finely regulated process called erythropoiesis that produces two million RBCs every second in healthy human being adults (Palis, 2014). The standard model of erythropoiesis starts with hematopoietic stem cells (HSCs) in the bone marrow (BM), giving rise to multipotent progenitors that continue to erythroid-committed precursors to mature RBC. This hierarchical relationship is, however, challenged, showing a greater plasticity for the cell's potential fates, with several studies in mice (Adolfsson et al., 2005) and recent new information in human (Notta et al., 2016).

Maturation from erythroid-committed precursors is called terminal erythropoiesis and occurs in the BM within erythroblastic islands, which consist of a central macrophage surrounded by erythroblasts, and ends in the blood stream where reticulocytes consummate their maturation within 1–ii days. During this phase, proerythroblasts (Pro-E) undergo morphological changes, such as cell size reduction and chromatin condensation, produce specific proteins, such as hemoglobin, and exhibit a reduced proliferative capacity to give rise to basophilic (Baso-E), polychromatophilic (Poly-E) and orthochromatophilic (Ortho-E) erythroblasts, successively. Even though several growth factors are known to regulate erythropoiesis, Epo is the main regulator of erythropoiesis driving RBC precursor proliferation and differentiation, preventing erythroblast apoptosis (Koury and Bondurant, 1990; Ji et al., 2011). The macrophage-erythroblast interaction in the BM is essential since macrophages facilitate proliferation and differentiation and provide atomic number 26 to the erythroblasts (de Dorsum et al., 2014).

At the end of the terminal maturation, mammalian erythroblasts expel their nuclei and lose all their organelles, such as the Golgi apparatus, endoplasmic reticulum (ER), mitochondria and ribosomes. After expelling its nucleus, the reticulocyte maturation continues, losing 20–30% of the cell surface (Waugh et al., 1997; Da Costa et al., 2001) and eliminating any remaining membrane-bound cytosolic organelles through an autophagy/exosome-combined pathway (Blanc et al., 2005).

While all-encompassing literature is done concerning the general mechanisms of erythropoiesis (Palis, 2014), this review focuses on the mechanisms and molecular actors involved during organelle clearance and membrane remodeling in order to produce fully functional biconcave mature RBCs. Figure ane summarizes the best characterized steps of organelle clearance throughout erythroblast terminal differentiation.

Figure 1. Terminal maturation of erythroblasts. (A) At the erythroblast stage, two Ulk1-mediated autophagic pathways are activated to allow organelle clearance: the Atg5/vii-dependent pathway with the proteolytic Atg4-dependent activation of MAPLC3, microtubule-associated protein 1 light channel three (LC3) and the Atg5/7-independent pathway, which is not related to the LC3 protein. LC3 activation allows its insertion into the phagophore membrane, starting the engulfment of organelles through the recognition of an ubiquitin signal or by the directly binding of specialized receptors at the organelle membrane. In non-erythroid cells, Rab9a is important for the germination of the phagophore during the Atg5/7-contained autophagic pathway. After the formation of the autophagosome, its fusion with the lysosome permits the deposition of organelles by hydrolytic enzymes. The enucleation process gives rise to the pyrenocyte and the reticulocyte, which nevertheless contains some organelles that must be eliminated for the final maturation into erythrocyte. (B) During this stage, unwanted membrane proteins, such as transferrin receptor (TfR), are internalized by endocytosis and expelled past exocytosis from multi-vesicular torso structures. Glycophorin A (GPA)/LC3 double-positive vesicles containing organelle remnants are also found in reticulocytes, suggesting cooperation between the endocytosis (GPA⁺) and autophagy (LC3⁺) pathways to eliminate organelles. How autophagosomes interact with multivesicular bodies (MVBs) following the same pathway of membrane protein recycling or budding directly from the plasma membrane later on fusion with endocytic vesicles, still, remains unknown.

Enucleation

The most spectacular attribute of mammalian erythropoiesis is the generation of enucleated cells. Enucleation occurs in orthochromatic erythroblasts producing two kinds of cells, the reticulocyte and the pyrenocyte [the nucleus surrounded by a tiny layer of cytoplasm and the plasma membrane (PM)]. Pyrenocytes are chop-chop eliminated past the macrophages of the erythroblastic island, where phosphatidylserine exposure acts as an "eat me" signal (Yoshida et al., 2005).

Among the changes occurring during final differentiation, cell bike arrest, chromatin and nuclear condensation and nuclear polarization are important for enucleation. In addition, nucleus expulsion is believed to be dependent on adhesion poly peptide reorganization beyond the PM and macrophage interactions (Lee et al., 2004; Soni et al., 2006). The transcription factor KFL1 is required for enucleation (Parkins et al., 1995; Magor et al., 2015), regulating the expression of cell bike proteins, deacetylases, caspases, and nuclear membrane proteins (Gnanapragasam et al., 2016; Gnanapragasam and Bieker, 2017).

Nuclear and chromatin condensation is essential for enucleation (Popova et al., 2009; Ji et al., 2010) and is dependent on the acetylation status of histones H3 and H4 nether the control of histone acetyl transferases (HATs) and histone deacetylases (HDACs). Accordingly, Gcn5, an Chapeau protein, is downward-regulated, and H3K9 and H4K5 histone acetylation decreases during mouse fetal erythropoiesis. In add-on, Gcn5 is up regulated past c-Myc, which is known to decrease during the late stage of the erythropoiesis (Jayapal et al., 2010). With the aforementioned model, the role of HDAC2 protein was shown to be essential non only for chromatin condensation merely also for the formation of the contractile actin ring (CAR), which is involved in nuclear pyknosis (Ji et al., 2010). Moreover, it was recently shown that major histones are released through a nuclear opening that is induced by caspase 3 action-dependent lamin B cleavage and chromatin condensation (Gnanapragasam and Bieker, 2017).

Many studies demonstrate the cell bicycle dependence of enucleation (Gnanapragasam and Bieker, 2017). Interestingly, the cyclin-induced E2F-2 transcription factor, which is a direct target of KLF1 during terminal erythropoiesis, appears to play a role in enucleation by inducing the expression of CRIK (Citron Rho-interacting kinase). Away from its regular targets related to microtubule arrangement and cytokinesis, CRIK participates in nuclear condensation (Swartz et al., 2017).

Cytoskeletal elements play an important office in erythroblast enucleation, acting in a like manner to cytokinesis just in an asymmetric way. Specifically, as observed past electron and immunofluorescence microscopy, actin filaments (F-actin) condensate behind the extruding nucleus to course the Automobile. The use of cytochalasin D, an F-actin inhibitor, causes the complete blockage of enucleation (Koury et al., 1989). Furthermore, the formation of the Motorcar is dependent on Rac1 GTPase and on mDia2, a Rho GTPase downstream effector, since down-regulating these two proteins disrupts the CAR formation and blocks erythroblast enucleation (Ji et al., 2008).

Regarding other cytoskeleton elements, the pharmacological inhibition of vimentin does not bear upon enucleation, which is in agreement with its decrease during human erythropoiesis (Dellagi et al., 1983). However, the deregulation of microtubules diminishes the enucleation rate. Microtubules form a handbasket around the nucleus (Koury et al., 1989), which is displaced well-nigh the PM at the late erythroblast stages, suggesting that this network must be essential for the polarization of the nucleus. Recently, the importance of the molecular motor dynein, which mediates unidirectional movement toward the minus finish of the microtubules, was shown. Furthermore, PI3K activity is induced by microtubule polymers, improves the polarization efficiency and promotes nuclear movement. Even so, PI3K inhibition does not block, but just delays, mice enucleation (Wang et al., 2012).

In 2010, Crispino's grouping observed, by electron microscopy, the formation of vesicles shut to the nuclear extrusion site in both principal murine and human erythroblasts, suggesting that some other mechanism contributes to enucleation. Additionally, every bit shown past genetic invalidation, clathrin is needed for the vesicle formation (Keerthivasan et al., 2010). More than recently, it was shown that survivin is required for erythroblast enucleation, but instead of acting on cytokinesis via the chromosome rider complex, survivin contributes to enucleation through an interaction with EPS15 and clathrin (Keerthivasan et al., 2012).

Conspicuously, nosotros are still at the beginning of unraveling the molecular players involved in the enucleation procedure. Moreover, every bit shown in Table ane, most of the molecular players were identified in mice, and nosotros are still lacking a demonstration that these players are also involved in human being erythropoiesis.

Table 1. Comparison between studies in human being or mice erythroid cells or in other cell models.

Mitochondrial Clearance

The principal mechanism for mitochondrial clearance is mitophagy, a selective type of autophagy that allows the degradation of damaged mitochondria. The importance of this process is highlighted past knowing that an impairment in mitochondrial part triggers an increase in reactive oxygen species production, which tin in turn cause harm to cellular components (proteins, nucleic acid, and lipids) and trigger jail cell death (Lee et al., 2012).

During regular autophagy processes, stress or nutrient deprivation activates APM-activated protein kinase (AMPK), triggering ii ubiquitin-dependent pathways (Effigy 1A). 1 of these allows the assembly of the phagophore and involves several autophagy-related proteins (Atg), such as Atg5 and Atg7. The other aims to actuate and lipidate LC3 (MAPLC3, microtubule-associated protein 1 light aqueduct 3) past Atg4, a redox regulated protein. Atg4 and Atg7 cooperate to conjugate LC3 onto phosphatidylethanolamine in the lipid bilayer of the membrane originated from the ER-mitochondria contact site (Tooze and Yoshimori, 2010; Hamasaki et al., 2013). The elongated phagophore is then recruited to engulf targets via adaptor proteins, containing an LC3-interacting region (LIR) that forms a double-membrane autophagosome, which will fuse with a lysosome, initiating the deposition of the autophagosome components.

Upon mitochondria damage or depolarization, the mitochondrial membrane proteins are exposed and deed as a beacon to recruit the phagophore membranes (Liu et al., 2014). An example is the PINK1 (P-X-induced kinase 1)-dependent recruitment of Parkin. Upon mitochondria depolarization, PINK1 accumulates at the OMM (outer mitochondrial membrane) and induces the mitochondrial translocation of Parkin, an RBR (band-in-between)-type E3 ubiquitin ligase past direct phosphorylation (Kim et al., 2008; Narendra et al., 2010). The stabilization of Parkin at the OMM leads to the poly-ubiquitination of many proteins, inducing mitochondria fission and mobility finish and the phagophore recruitment past interacting with p62/SQSTM1, a LIR containing protein (Geisler et al., 2010). Dissimilar regular mitophagy induction, targeted mitochondria, during erythroblast maturation, are fully functional. BNIP3L/NIX, a BH3-but integral OMM protein commencement identified in mouse reticulocytes, appears to exist the major mitochondrial protein involved during final differentiation (Schweers et al., 2007; Sandoval et al., 2008). This protein is upregulated during erythropoiesis and induces mitochondrial membrane depolarization and membrane conjugated LC3 recruitment to the mitochondria (Aerbajinai et al., 2003; Novak et al., 2010). Nix action is not mediated by its BH3 domain but rather seems to be due to a cytoplasmic short linear motif, acting as a cellular signal to recruit other proteins (Zhang et al., 2012). Nevertheless, whether Naught-induced mitochondrial depolarization activates the Parkin-dependent pathway is even so unknown (Yuan et al., 2017).

Recently, other mitochondrial receptors were plant to participate in mitophagy, such every bit FUNDC1, induced by MARCH5, an E3 ubiquitin ligase acting in hypoxic condition (Chen et al., 2017), Bcl2-L-13 (Murakawa et al., 2015), optineurin (Wong and Holzbaur, 2014), and Prohibitin 2 (Wei et al., 2017). It remains unknown whether they play a role in erythroid maturation.

Canonical Atg proteins also participate in terminal maturation. In man erythropoiesis, LC3 cleavage is under the control of the endopeptidase Atg4 and is needed for autophagosome maturation (Betin et al., 2013). In mice, Ulk1 (Atg1) expression correlates with terminal differentiation and participates in mitochondria and ribosome elimination (Chan et al., 2007; Kundu et al., 2008). The ubiquitination-dependent pathway also plays a function in reticulocyte maturation but is not essential. Indeed, in Atg7^−/− reticulocytes, mitochondrial clearance is only partially afflicted (Zhang and Ney, 2009; Zhang et al., 2009). Still, Nix and Ulk1 activation appears to be essential (Mortensen et al., 2010; Honda et al., 2014), suggesting the coexistence of both Atg5/Atg7-dependent and contained pathways during terminal differentiation.

Some studies suggest that the Atg5/vii-independent degradation of mitochondria involves endosomal trafficking regulatory Rab proteins. Autophagosomes, formed in a Ulk1-dependent pathway, fuse with Golgi-derived vesicles and tardily endosomes in a Rab9a-dependent mode before they are targeted to the lysosomes (Wang et al., 2016). Interestingly, Rab proteins were also recently shown to be involved in mitochondria removal in a complete autophagy-independent pathway. Depolarized mitochondria appear to be engulfed in Rab5-positive endosomes that mature into Rab7-positive late endosomes and then fuse with lysosomes (Hammerling et al., 2017a,b). Dissimilar canonical autophagy, which involves the surrounding of a ubiquitin-decorated target by a double membrane structure, the entire mitochondria appears to be engulfed by an early endosome membrane invagination through the ESCRT machinery. Whether this might also occur in maturing erythroblasts is not known.

Mitophagy also appears to be transcriptionally regulated. Indeed, hemin-dependent differentiation of an erythroid cell line shows features of mitophagy (Fader et al., 2016). The NF-E2 transcription cistron involved in globin factor expression also regulates mitophagy through the regulation of Aught and Ulk1 genes (Gothwal et al., 2016; Lupo et al., 2016). Another key regulator is the KRAB/KAP1-miRNA regulatory cascade, which acts as an indirect repressor of mitophagy genes in mice besides as in human being cells, probably past the down and up regulation of a series of miRNAs, such equally miR-351 that targets Nix (Barde et al., 2013).

In parallel to the autophagic pathway, cytosolic deposition seems to occur during reticulocyte maturation. 15-lipoxygenase (15-LOX), an enzyme that catalyzes the dioxygenation of polyunsaturated fatty acids, is translationally inhibited until the reticulocyte stage and acts to permeabilize organelle membranes, allowing proteasome access and deposition. Interestingly, just mitochondria emptying is afflicted, while ribosome clearance remains efficient when using a lipoxygenase inhibitor (Grüllich et al., 2001). This mechanism is still controversial, as fifteen-LOX might also act in the autophagy pathway as an OMM pH gradient disruptor that can induce mitophagy (Vijayvergiya et al., 2004), and on the oxidation of phospholipids conjugating with LC3 during the autophagosome formation; even so, these features, as shown in Tabular array ane were not demonstrated in erythroid cells yet (Morgan et al., 2015).

Ribosomes and Other Organelles

In general, autophagy plays an essential function in the emptying of other organelles, such as lysosomes, peroxisomes and ER. However, the literature presents only very few studies in erythroid cells (Table 1).

While Nix is required for mitochondria removal, Ulk1 is involved in ribosome and mitochondria degradation (Schweers et al., 2007; Kundu et al., 2008; Sandoval et al., 2008). Similarly, an efficient clearance of ribosomes and ER and the inhibition of mitophagy was observed in Atg7^−/− mice (Mortensen et al., 2010). These data suggest that non-autophagic or Atg7-independent autophagic pathways might exist for the elimination of other organelles (Figure 1A).

In non-erythroid cells from mammals, it was proposed that peroxisomes are eliminated past three unlike pathways: macroautophagy (Iwata, 2006), xv-LOX mediated (Yokota et al., 2001) and the peroxisomal Lon proteases (Yokota et al., 2008). Furthermore, the autophagic degradation of lysosomes (lysophagy) was recently identified in HeLa cells where it is mediated past ubiquitination and involves p62 protein (Hung et al., 2013). The similarities betwixt pexophagy/lysophagy and mitophagy in not-erythroid cells advise that autophagy pathways might also be involved in erythroblast last maturation.

Later on enucleation, reticulocytes mature in the bone marrow (R1) then leave in the blood stream (R2) to consummate the process. While the degradation of organelles starts at the fourth dimension of enucleation, the emptying of mRNA occurs in the blood stream and is mediated by ribonucleases, generating nucleotides that are degraded by the erythroid pyrimidine nucleotidase. This elimination is crucial, as the deficiency in this enzyme causes hemolytic anemia (Valentine et al., 1974). mRNAs in R2 reticulocytes mainly belong to iii overlapping categories: ship, metabolic and bespeak transduction (Lee et al., 2014), and their presence is essential to reach the mature RBC stage. This supports the importance of the exosome pathway for the final maturation into RBCs with an agile elimination of other subcellular components.

Exocytosis and Membrane Remodeling

Exosomes are small vesicles that are secreted into the extracellular medium from diverse kind of cells. PM invaginations form early endosomes that engulf diverse targets forming multivesicular bodies (MVB, late endosomes) that eventually fuse with the PM and release exosomes. In reticulocytes, this pathway is thought to be involved in prison cell book and membrane remodeling to reduce book and remove unwanted membrane proteins. This was beginning discovered in sheep reticulocytes where transferrin receptor (TfR) is first internalized into modest vesicles of 100–200 nm earlier existence engulfed into the MVBs (Pan et al., 1985; Johnstone et al., 1989). The internalization step is clathrin-dependent, and the deposition is lysosome-independent and occurs by exocytosis after the fusion of the MVBs with the PM as shown in Figure 1B (Killisch et al., 1992). This process is required for the final elimination of other membrane proteins that are essential for the reticulocyte but are absent in the mature jail cell. Proteins such as aquaporin-1 (AQP1) (Blanc et al., 2009), α4β1 integrin (Rieu et al., 2000), glucose transporter and acetylcholinestarase (Johnstone et al., 1987) are found in glycophorine-A (GPA) positive endosomes while cytoskeletal proteins, such as actin or spectrin have never been found in these endosomes (Liu et al., 2010).

While enough of evidence notes the role of autophagy in removing organelles during terminal maturation, the degradation step itself shows discrepancies with approved proteolysis involving lysosomal proteins because of the disappearance of the lysosomal compartment during the maturation and removal of LAMP2 by exocytosis (Barres et al., 2010). Recently, GPA-positive endosomes were found to express LC3 at the endosome membrane, suggesting the cooperation of both autophagy and exocytosis in the removal of remnant organelles in R2 reticulocytes. These hybrid vesicles contain mitochondria, Golgi and lysosomes might be formed by the fusion of the outer-membrane of the autophagosome and the PM derived endosome (Griffiths et al., 2012). The exocytosis of this vesicle might be favored by the spleen, as splenectomized patients present large vacuoles within reticulocytes (Holroyde and Gardner, 1970).

It should exist pointed out the importance of lipids domain such as cholesterol and sphingomyelin-enriched domains in the PM remodeling, as they were discover both in membrane vesiculation specific sites (Leonard et al., 2017).

Decision

Even if all the animal models used to place the molecular players involved during final differentiation exhibit maturation defects and anemia, links between organelle clearance and homo hematological diseases are still mostly unknown. Erythroid disorders, such as β-thalassemia and myelodysplastic syndrome (MDS), are characterized by ineffective hematopoiesis, anemia, dissociation betwixt proliferation and differentiation of progenitor cells and the inefficient elimination of aggregated protein (Arber et al., 2016; Taher et al., 2017). Indeed, defects in reticulocyte maturation and autophagy are identified in HbE/β-thalassemia patients (Lithanatudom et al., 2011; Khandros et al., 2012; Butthep et al., 2015), and enucleation defects are constitute in MDS patients (Garderet et al., 2010; Park et al., 2016). Impaired autophagy is involved in cytosolic toxic Lyn accumulation and mitochondria and lysosome deposition delay in chorea-acanthocytosis (Lupo et al., 2016). The use of autophagy modulators is beneficial in the case of SCD or β-thalassemia (Franco et al., 2014; Jagadeeswaran et al., 2017). Moreover, anemia in Pearson's syndrome was recently linked to incomplete mitochondrial clearance from reticulocytes (Palis, 2014) and an asynchronization of iron loading (Ahlqvist et al., 2015), while sickle cells patients showed an accumulation of proteins in their erythrocytes suggesting a defect in exosomal pathway (De Franceschi, 2009; Carayon et al., 2011).

Unraveling the molecular mechanisms and interplays ruling erythroblast final maturation would be priceless in hematological disease therapy. However, much of our knowledge regarding human erythropoiesis is based on fauna models and/or ex vivo cultured human being progenitor cells (Table ane). Great care should be applied when interpreting results, considering the important differences between mouse and human erythropoiesis as well as the in vivo and in vitro environments, as highlighted in the extensive transcriptome analysis beyond a terminal erythroid differentiation study (An et al., 2014).

Author Contributions

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

Funding

This report was supported by grants from Laboratory of Excellence GR-Ex, reference ANR-xi-LABX-0051. The labex GR-Ex is funded past the plan "Investissements d'avenir" of the French National Research Agency, reference ANR-eleven-IDEX-0005-02.

Conflict of Interest Argument

The authors declare that the research was conducted in the absenteeism of whatever commercial or financial relationships that could be construed every bit a potential conflict of interest.

Acknowledgments

MM is funded by the European Wedlock'south Horizon 2020 inquiry and innovation programme under the Marie Skłodowska-Curie grant agreement No. 665850. Nosotros thank I. Marginedas-Freixa and C. Hattab for helpful discussions.

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