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Blood. 2017 Aug 31;130(9):1144-1155. doi: 10.1182/blood-2017-05-787051. Epub 2017 Jul 20.

Tropomodulin 1 controls erythroblast enucleation via regulation of F-actin in the enucleosome.

Author information

1
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA.
2
Center for Autoimmune and Musculoskeletal Disorders, Feinstein Institute for Medical Research, Manhasset, NY.
3
Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA; and.
4
Department of Molecular Medicine and.
5
Department of Pediatrics, Hofstra-Northwell School of Medicine, Hempstead, NY.

Abstract

Biogenesis of mammalian red blood cells requires nuclear expulsion by orthochromatic erythoblasts late in terminal differentiation (enucleation), but the mechanism is largely unexplained. Here, we employed high-resolution confocal microscopy to analyze nuclear morphology and F-actin rearrangements during the initiation, progression, and completion of mouse and human erythroblast enucleation in vivo. Mouse erythroblast nuclei acquire a dumbbell-shaped morphology during enucleation, whereas human bone marrow erythroblast nuclei unexpectedly retain their spherical morphology. These morphological differences are linked to differential expression of Lamin isoforms, with primary mouse erythroblasts expressing only Lamin B and primary human erythroblasts only Lamin A/C. We did not consistently identify a continuous F-actin ring at the cell surface constriction in mouse erythroblasts, nor at the membrane protein-sorting boundary in human erythroblasts, which do not have a constriction, arguing against a contractile ring-based nuclear expulsion mechanism. However, both mouse and human erythroblasts contain an F-actin structure at the rear of the translocating nucleus, enriched in tropomodulin 1 (Tmod1) and nonmuscle myosin IIB. We investigated Tmod1 function in mouse and human erythroblasts both in vivo and in vitro and found that absence of Tmod1 leads to enucleation defects in mouse fetal liver erythroblasts, and in CD34+ hematopoietic stem and progenitor cells, with increased F-actin in the structure at the rear of the nucleus. This novel structure, the "enucleosome," may mediate common cytoskeletal mechanisms underlying erythroblast enucleation, notwithstanding the morphological heterogeneity of enucleation across species.

PMID:
28729432
PMCID:
PMC5580276
DOI:
10.1182/blood-2017-05-787051
[Indexed for MEDLINE]
Free PMC Article

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