Insights on the Role of PGRMC1 in Mitotic and Meiotic Cell Division

Abstract

During mitosis, chromosome missegregation and cytokinesis defects have been recognized as hallmarks of cancer cells. Cytoskeletal elements composing the spindle and the contractile ring and their associated proteins play crucial roles in the faithful progression of mitotic cell division. The hypothesis that PGRMC1, most likely as a part of a yet-to-be-defined complex, is involved in the regulation of spindle function and, more broadly, the cytoskeletal machinery driving cell division is particularly appealing. Nevertheless, more than ten years after the preliminary observation that PGRMC1 changes its localization dynamically during meiotic and mitotic cell division, this field of research has remained a niche and needs to be fully explored. To encourage research in this fascinating field, in this review, we will recap the current knowledge on PGRMC1 function during mitotic and meiotic cell division, critically highlighting the strengths and limitations of the experimental approaches used so far. We will focus on known interacting partners as well as new putative associated proteins that have recently arisen in the literature and that might support current as well as new hypotheses of a role for PGRMC1 in specific spindle subcompartments, such as the centrosome, kinetochores, and the midzone/midbody.

Keywords: cell division; cytokinesis; cytoskeleton; meiosis; mitosis; progesterone receptor membrane component 1; spindle.

Figure 2

Images showing immunofluorescence and in situ proximity ligation assay (PLA) to assess the association of PGRMC1 and myosin in in vitro cultured bovine granulosa cells. Analysis was conducted as described in [113,163] with proper combination of antibodies, which were rabbit anti-PGRMC1 (Sigma Aldric Prestige antibody HPA002877, 1:50) and mouse monoclonal non-muscle myosin IIA antibody (2B3) (Novus Biological H00004627-M03, 1:100). Nuclei were counterstained with DAPI. Data were presented at the 51st Annual Meeting of the Society for the Study of Reproduction, 10–13 July 2018, New Orleans, Louisiana, USA, and the 2018 Gordon Research Conference in Mammalian Reproduction, 29 July–3 August 2018, Barga, Lucca, IT.

Figure 1

Schematic representation of the key features of mitotic cell division and cytokinesis. (A) During prophase/prometaphase, cell rounding occurs due to the rearrangement of the actin cytoskeleton. The duplicated centrosomes migrate around the nucleus, nucleate the spindle microtubules, and organize the spindle poles. The nuclear envelope breaks down, and the spindle microtubules promote mitotic chromosome congression. (B) During metaphase, the spindle consists of astral microtubules, which link spindle poles to the cell cortex; chromosomal and kinetochore microtubules, which overall link the chromosomes to poles; and interpolar microtubules, which link the two poles. The proteins of the chromosomal passenger complex (CPC) are concentrated at the centromere. (C) During anaphase, the chromatids segregate. The division plane is determined by a mechanism involving interactions between the cortex and the spindle. The cleavage furrow containing an actomyosin ring assembles and begins to contract. The CPC relocalizes at the central spindle. (D) During telophase/abscission, the nuclear envelopes reassemble around the decondensing chromosomes. The contractile ring contracts further, leading to the ingression of the furrow and constricting interpolar microtubules of the midzone into a restricted area (midbody). The CPC is concentrated in the midbody. During abscission, the furrow “seals” and divides the daughter cells via a mechanism thought to involve vesicle transport/exocytosis. Substantial rearrangements of the membranous compartment occur at all stages. Membrane vesicles are found associated with the spindle and participate in membrane remodeling during abscission. Image inspired by and modified from [7,31,33]. Created with BioRender.com (access on 10 November 2022).

Figure 3

Images showing immunofluorescent and in situ proximity ligation assay to assess the association of PGRMC1 and clathrin in in vitro cultured bovine granulosa cells. Analysis was conducted as described in [113,163] with proper combination of antibodies, which were rabbit anti-PGRMC1 (Sigma Aldric Prestige antibody HPA002877, 1:50) and mouse monoclonal anti-clathrin heavy-chain antibody (X22) (ThermoFisher Scientific, 1:500). Nuclei were counterstained with DAPI. Data were presented at the 48th Annual Meeting of the Society for the Study of Reproduction, 18–22 June 2015, San Juan, Puerto Rico, USA.

Figure 4

Images showing immunofluorescent and in situ proximity ligation assay to assess the association of PGRMC1 and clathrin in in vitro cultured bovine granulosa cells undergoing mitotic division. Analysis was conducted as described in [113,163] with proper combination of antibodies, which were rabbit anti-PGRMC1 (Sigma Aldric Prestige antibody HPA002877, 1:50) and mouse monoclonal anti-clathrin heavy-chain antibody (X22) (ThermoFisher Scientific, 1:500). Nuclei were counterstained with DAPI. Controls were performed by eliminating one of the two primary antibodies, as shown in Supplementary Figure S1. Data were presented at the 48th Annual Meeting of the Society for the Study of Reproduction, 18–22 June 2015, San Juan, Puerto Rico, USA.