Nature Cell Biology, 10 3 , Communications and Public Affairs Phone: Email: newsroom wi. The Lodish Lab focused on important areas at the interface between molecular cell biology and medicine.
Whitehead Institute researchers have rewritten the timeline for when and how embryonic cells commit to becoming sex cells, the cells that produce eggs and sperm, and gained insights into the development of testicular cancer. Whitehead Institute researchers have discovered that particular signaling pathways, which transmit environmental cues and effect changes in gene expression, rely on phase-separated condensates to find, occupy, and activate the right genes in each cell type.
How red blood cells nuke their nuclei. Written by Cristin Carr. February 10, Copied to clipboard. Intrigued by immortality. March 16, See more from our free eBook library. Information about carbon monoxide poisoning from the Mayo Clinic. Information about sickle cell anemia from the Mayo Clinic. Overview of Blood. Granular Myeloid White Blood Cells. Agranular Myeloid White Blood Cells. Lymphoid White Blood Cells. When you select "Subscribe" you will start receiving our email newsletter.
Use the links at the bottom of any email to manage the type of emails you receive or to unsubscribe. See our privacy policy for additional details. Learn Site. No Nucleus? Red blood cells take seven days to develop from stem cells called hemocytoblasts. Inactivated platelets are irregular disc-shaped structures.
Activated platelets are round with projections. Platelets clump at sites of injury to prevent blood loss. Visible Body Biology Learn more. 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 organization and cytokinesis, CRIK participates in nuclear condensation Swartz et al. Cytoskeletal elements play an important role in erythroblast enucleation, acting in a similar manner to cytokinesis but in an asymmetric way. Specifically, as observed by electron and immunofluorescence microscopy, actin filaments F-actin condensate behind the extruding nucleus to form the CAR. The use of cytochalasin D, an F-actin inhibitor, causes the complete blockage of enucleation Koury et al.
Regarding other cytoskeleton elements, the pharmacological inhibition of vimentin does not affect enucleation, which is in agreement with its decrease during human erythropoiesis Dellagi et al.
However, the deregulation of microtubules diminishes the enucleation rate. Microtubules form a basket around the nucleus Koury et al. Recently, the importance of the molecular motor dynein, which mediates unidirectional movement toward the minus end of the microtubules, was shown.
Furthermore, PI3K activity is induced by microtubule polymers, improves the polarization efficiency and promotes nuclear movement. However, PI3K inhibition does not block, but only delays, mice enucleation Wang et al.
In , Crispino's group observed, by electron microscopy, the formation of vesicles close to the nuclear extrusion site in both primary murine and human erythroblasts, suggesting that another mechanism contributes to enucleation.
Additionally, as shown by genetic invalidation, clathrin is needed for the vesicle formation Keerthivasan et al. More recently, it was shown that survivin is required for erythroblast enucleation, but instead of acting on cytokinesis via the chromosome passenger complex, survivin contributes to enucleation through an interaction with EPS15 and clathrin Keerthivasan et al. Clearly, we are still at the beginning of unraveling the molecular players involved in the enucleation process.
Moreover, as shown in Table 1 , most of the molecular players were identified in mice, and we are still lacking a demonstration that these players are also involved in human erythropoiesis. Table 1. Comparison between studies in human or mice erythroid cells or in other cell models. The main 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 by knowing that an impairment in mitochondrial function triggers an increase in reactive oxygen species production, which can in turn cause damage to cellular components proteins, nucleic acid, and lipids and trigger cell death Lee et al. One of these allows the assembly of the phagophore and involves several autophagy-related proteins Atg , such as Atg5 and Atg7. 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, ; Hamasaki et al.
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 degradation of the autophagosome components. Upon mitochondria damage or depolarization, the mitochondrial membrane proteins are exposed and act as a beacon to recruit the phagophore membranes Liu et al.
Unlike regular mitophagy induction, targeted mitochondria, during erythroblast maturation, are fully functional. This protein is upregulated during erythropoiesis and induces mitochondrial membrane depolarization and membrane conjugated LC3 recruitment to the mitochondria Aerbajinai et al. 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.
However, whether Nix-induced mitochondrial depolarization activates the Parkin-dependent pathway is still unknown Yuan et al. It remains unknown whether they play a role in erythroid maturation. Canonical Atg proteins also participate in terminal maturation.
In human erythropoiesis, LC3 cleavage is under the control of the endopeptidase Atg4 and is needed for autophagosome maturation Betin et al. In mice, Ulk1 Atg1 expression correlates with terminal differentiation and participates in mitochondria and ribosome elimination Chan et al. The ubiquitination-dependent pathway also plays a role in reticulocyte maturation but is not essential.
However, Nix and Ulk1 activation appears to be essential Mortensen et al. Autophagosomes, formed in a Ulk1-dependent pathway, fuse with Golgi-derived vesicles and late endosomes in a Rab9a-dependent manner before they are targeted to the lysosomes Wang et al. 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. Unlike 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. The NF-E2 transcription factor involved in globin gene expression also regulates mitophagy through the regulation of Nix and Ulk1 genes Gothwal et al. In parallel to the autophagic pathway, cytosolic degradation seems to occur during reticulocyte maturation. This mechanism is still controversial, as LOX might also act in the autophagy pathway as an OMM pH gradient disruptor that can induce mitophagy Vijayvergiya et al.
In general, autophagy plays an essential role in the elimination 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.
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 by three different pathways: macroautophagy Iwata, , LOX mediated Yokota et al. Furthermore, the autophagic degradation of lysosomes lysophagy was recently identified in HeLa cells where it is mediated by ubiquitination and involves p62 protein Hung et al.
After enucleation, reticulocytes mature in the bone marrow R1 and then exit in the blood stream R2 to complete the process. While the degradation of organelles starts at the time of enucleation, the elimination 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.
This supports the importance of the exosome pathway for the final maturation into RBCs with an active elimination of other subcellular components.
Exosomes are small vesicles that are secreted into the extracellular medium from various kind of cells. PM invaginations form early endosomes that engulf various 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 cell volume and membrane remodeling to reduce volume and remove unwanted membrane proteins. This was first discovered in sheep reticulocytes where transferrin receptor TfR is first internalized into small vesicles of — nm before being engulfed into the MVBs Pan et al.
The internalization step is clathrin-dependent, and the degradation is lysosome-independent and occurs by exocytosis after the fusion of the MVBs with the PM as shown in Figure 1B Killisch et al. This process is required for the final elimination of other membrane proteins that are essential for the reticulocyte but are absent in the mature cell. Proteins such as aquaporin-1 AQP1 Blanc et al. While plenty of evidence notes the role of autophagy in removing organelles during terminal maturation, the degradation step itself shows discrepancies with canonical proteolysis involving lysosomal proteins because of the disappearance of the lysosomal compartment during the maturation and removal of LAMP2 by exocytosis Barres et al.
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.
The exocytosis of this vesicle might be favored by the spleen, as splenectomized patients present large vacuoles inside reticulocytes Holroyde and Gardner, It should be pointed out the importance of lipids domain such as cholesterol and sphingomyelin-enriched domains in the PM remodeling, as they were find both in membrane vesiculation specific sites Leonard et al.
Even if all the animal models used to identify the molecular players involved during terminal differentiation exhibit maturation defects and anemia, links between organelle clearance and human hematological diseases are still mostly unknown.
Impaired autophagy is involved in cytosolic toxic Lyn accumulation and mitochondria and lysosome degradation delay in chorea-acanthocytosis Lupo et al. Moreover, anemia in Pearson's syndrome was recently linked to incomplete mitochondrial clearance from reticulocytes Palis, and an asynchronization of iron loading Ahlqvist et al. Unraveling the molecular mechanisms and interplays ruling erythroblast terminal maturation would be priceless in hematological disease therapy.
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 across a terminal erythroid differentiation study An et al.
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank I. Marginedas-Freixa and C. Hattab for helpful discussions. Adolfsson, J. Cell , — Aerbajinai, W. The proapoptotic factor Nix is coexpressed with Bcl-xL during terminal erythroid differentiation. Blood , — Ahlqvist, K. MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction. An, X. Global transcriptome analyses of human and murine terminal erythroid differentiation.
Arber, D. The revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Barde, I. Science , — Barres, C. Galectin-5 is bound onto the surface of rat reticulocyte exosomes and modulates vesicle uptake by macrophages.
Betin, V. Autophagy facilitates organelle clearance during differentiation of human erythroblasts: evidence for a role for ATG4 paralogs during autophagosome maturation. Autophagy 9, — Blanc, L. Exosome release by reticulocytes—an integral part of the red blood cell differentiation system.
Blood Cells. The water channel aquaporin-1 partitions into exosomes during reticulocyte maturation: implication for the regulation of cell volume. Butthep, P. Elevated erythropoietin and cytokines levels are related to impaired reticulocyte maturation in thalassemic patients.
Carayon, K. Proteolipidic composition of exosomes changes during reticulocyte maturation. Chan, E. Chen, Z. Autophagy 13, —
0コメント