Centrosome function is critical during terminal erythroid differentiation

Abstract

Red blood cells are produced by terminal erythroid differentiation, which involves the dramatic morphological transformation of erythroblasts into enucleated reticulocytes. Microtubules are important for enucleation, but it is not known if the centrosome, a key microtubule-organizing center, is required as well. Mice lacking the conserved centrosome component, CDK5RAP2, are likely to have defective erythroid differentiation because they develop macrocytic anemia. Here, we show that fetal liver-derived, CDK5RAP2-deficient erythroid progenitors generate fewer and larger reticulocytes, hence recapitulating features of macrocytic anemia. In erythroblasts, but not in embryonic fibroblasts, loss of CDK5RAP2 or pharmacological depletion of centrosomes leads to highly aberrant spindle morphologies. Consistent with such cells exiting mitosis without chromosome segregation, tetraploidy is frequent in late-stage erythroblasts, thereby giving rise to fewer but larger reticulocytes than normal. Our results define a critical role for CDK5RAP2 and centrosomes in spindle formation specifically during blood production. We propose that disruption of centrosome and spindle function could contribute to the emergence of macrocytic anemias, for instance, due to nutritional deficiency or exposure to chemotherapy.

Macrocytic anemias

“…Deficiency of cyclin D3 [33], which controls terminal TED cell divisions, profoundly increases red cell size, suggesting that interrupted or delayed cell cycle progression in erythroid progenitors/precursors plays a role in macrocytosis development. Also, deficiencies in centrosome components that delay mitotic spindle formation in erythroid precursors cause macrocytosis [34 ▪ ]. A murine model of the mutation in splicing factor 3B, subunit 1 (Sf3b1 K700E ), which is commonly heterozygous in patients with macrocytic anemia in MDS, demonstrated that this mutation inhibited erythroid progenitor G 0 /G 1 transition leading to development of macrocytic anemia without associated apoptosis, indicating that interrupted and/or delayed cell cycle progression alone can cause macrocytic anemia [35].…”

Centrioles generate two scaffolds with distinct biophysical properties to build mitotic centrosomes

“…Cnn and SPD-5 have no obvious sequence homology, but they are both large coiled-coil-rich proteins that can assemble into large scaffolding structures (Woodruff et al, 2017; Feng et al, 2017; Nakajo et al, 2022). This pathway appears to be widely conserved, and vertebrate homologues of Spd-2/SPD-2 (CEP192) (Zhu et al, 2008; Gomez-Ferreria et al, 2007; Joukov et al, 2010; Chinen et al, 2021), Polo/PLK-1 (PLK1) (Lane and Nigg, 1996; Haren et al, 2009; Lee and Rhee, 2011; Joukov et al, 2014; Meng et al, 2015) and Cnn (CDK5RAP2/CEP215) (Fong et al, 2008; Choi et al, 2010; Lizarraga et al, 2010; Barr et al, 2010; Tátrai and Gergely, 2022), have all been implicated in mitotic centrosome assembly.…”

Exact centriole counts are critical for B cell development but not function

“…In hematopoietic cells, centrosomes exert functions that go beyond mitotic spindle pole formation and include erythroblast enucleation (Tátrai & Gergely, 2022), control of asymmetric cell division in lymphocytes (Barnett et al , 2012; Liedmann et al , 2022), immunological synapse formation (Dieckmann et al , 2016), as well as cell dendritic cell (DC) migration (Weier et al , 2022). Moreover, extra centrosomes have been documented during terminal differentiation of DCs to enhance effective helper T cell activation (Weier et al ., 2022), and in microglia, extra centrosomes increase their efferocytosis rates (Möller et al , 2022).…”