Aurora kinase A is essential for meiosis in mouse oocytes

Abstract

The Aurora protein kinases are well-established regulators of spindle building and chromosome segregation in mitotic and meiotic cells. In mouse oocytes, there is significant Aurora kinase A (AURKA) compensatory abilities when the other Aurora kinase homologs are deleted. Whether the other homologs, AURKB or AURKC can compensate for loss of AURKA is not known. Using a conditional mouse oocyte knockout model, we demonstrate that this compensation is not reciprocal because female oocyte-specific knockout mice are sterile and their oocytes fail to complete meiosis I. In determining the AURKA-specific functions, we demonstrate that its first meiotic requirement is to activate Polo-like kinase 1 at microtubule organizing centers (MTOCs; meiotic spindle poles). This activation induces fragmentation of the MTOCs, a step essential for building a bipolar spindle. The next step that requires AURKA is building the liquid-like spindle domain that involves TACC3. Finally, we find that AURKA is also required for anaphase I onset to trigger cohesin cleavage in an APC/C independent manner. We conclude that AURKA has multiple functions essential to completing MI that are distinct from AURKB and AURKC.Author SummaryFemale gametes, oocytes, are uniquely prone to chromosome segregation errors in meiosis I that are associated with early miscarriages. The Aurora protein kinases are essential to control chromosome segregation in all cell types. During mitosis, Aurora kinase A (AURKA) regulates the building of the spindle, the machinery responsible for pulling chromosomes apart. Here, we use a genetic approach to demonstrate that AURKA is essential for meiosis I in mouse oocytes. AURKA is required at multiple steps in meiosis I, first to trigger fragmentation of protein structures that make up the two ends of the meiotic spindle, later to regulate building of a specialized phase-separated spindle domain, and finally to trigger efficient cleavage of cohesin, the molecular glue that holds chromosomes together until anaphase onset. These findings are the first demonstration of distinct Aurora kinase function that cannot be compensated for by the other two homologs. Therefore, this mouse model is excellent tool for pinpointing specific Aurora kinase functions and identifying AURKA target proteins critical for chromosome segregation in meiosis I.

Kr-h1 maintains distinct caste-specific neurotranscriptomes in response to socially regulated hormones

“…As expected from their different functional status, 7,014 genes were differentially expressed in ovaries from control mature workers versus gamergates, including S2. Article markers of cell proliferation and ovary activation aurA, fs(1)Ya, and cort (Blengini et al, 2021;Chu et al, 2001;Lin and Wolfner, 1991), which were greatly upregulated in gamergates (Figure S7B, red; Table S1). Loss of Kr-h1 in the brain resulted in 559 significantly affected genes in the ovaries of mature workers and 2,751 in the ovaries of mature gamergates (Figure 6C).…”

Aurora B/C-dependent phosphorylation promotes Rec8 cleavage in mammalian oocytes

“…Loss of Aurora B/C can be complemented in part by Aurora A 21 , and complete loss of Aurora A interferes with proper spindle formation 22,23 , leading to a cell cycle arrest in metaphase I 23 . To address whether Aurora A is also required for chromosome segregation in meiosis I, we treated oocytes with the Aurora A inhibitor MLN8237 24 from entry into meiosis I onwards.…”

“…To address whether Aurora A is also required for chromosome segregation in meiosis I, we treated oocytes with the Aurora A inhibitor MLN8237 24 from entry into meiosis I onwards. Such as Aurora A knock-out oocytes, MLN8237treated oocytes arrested in metaphase I, indicating that inhibition of Aurora A was efficient 22,23 (Figure S1A). We added the Mps1 inhibitor Reversine to override the SAC arrest 25 which is at least partially responsible for the metaphase I arrest induced by Aurora A inhibition 23 , and performed chromosome spreads 14 hours later.…”

Aurora B/C-dependent phosphorylation promotes Rec8 cleavage in mammalian oocytes

“…Such as Aurora A knock-out oocytes, MLN8237treated oocytes arrested in metaphase I, indicating that inhibition of Aurora A was efficient [22,23] (Figure S1a). We added the Mps1 inhibitor Reversine to override the SAC arrest [25] which is at least partially responsible for the metaphase I arrest induced by Aurora A inhibition [23], and performed chromosome spreads 14 hours later. Figure S1a shows that inhibition of Aurora A and simultaneously overriding the SAC arrest with Reversine rescued PB extrusion in 40 % of MLN8237 treated oocytes, similar to previously published data [23].…”

“…We added the Mps1 inhibitor Reversine to override the SAC arrest [25] which is at least partially responsible for the metaphase I arrest induced by Aurora A inhibition [23], and performed chromosome spreads 14 hours later. Figure S1a shows that inhibition of Aurora A and simultaneously overriding the SAC arrest with Reversine rescued PB extrusion in 40 % of MLN8237 treated oocytes, similar to previously published data [23]. Importantly, MLN8237 treated oocytes that extruded a PB also segregated chromosomes (Figure S1b).…”