Terminally differentiated postmitotic cells such as mature neurons and glia are long-lived and must cope with the accumulation of damage over the course of an animal’s lifespan. The mechanisms used by such long-lived cells to deal with aging-related damage are poorly understood. The brain of the fruit fly Drosophila melanogaster is an ideal context to examine this since the fly has a relatively short lifespan and the adult fly brain is nearly entirely postmitotic with well understood development and excellent tools for genetic manipulations.

The adult central nervous system of Drosophila melanogaster comprises ~110,000 cells, most of which are generated in the larval and early pupal stages of development from various progenitor cell types (Truman and Bate, 1988; White and Kankel, 1978). By late metamorphosis, the Drosophila pupal brain is normally completely non-cycling and negative for markers of proliferation such as thymidine analog incorporation and mitotic markers (Awasaki et al., 2008; Pahl et al., 2019; Siegrist et al., 2010).

In the adult, very little neurogenesis and gliogenesis are normally observed (Awasaki et al., 2008; Ito and Hotta, 1992; von Trotha et al., 2009). A population of about 40 adult neural progenitors has been reported in the optic lobe and a population of glial progenitors has been reported in the central brain (Fernández-Hernández et al., 2013; Foo et al., 2017). Upon damage or cell loss, hallmarks of cycling have been shown to be activated, although the overall level of proliferation in the adult brain remains very low (Crocker et al., 2020; Fernandez-Hernandez et al., 2019; Fernández-Hernández et al., 2013; Foo et al., 2017; Li et al., 2020). Thus, the brain of the adult fly is thought to be almost entirely postmitotic with most cells in G0 with a diploid (2C) DNA content. One known exception to this are the cells that constitute the ‘blood-brain barrier’ of Drosophila.

The ‘blood-brain barrier’ in Drosophila is made up of specialised cells called the Sub-perineurial glia (SPGs). These cells are very few in number and achieve growth without cell division by employing variant cell cycles termed endocycles, that involve DNA replication without karyokinesis or cytokinesis, as well as endomitotic cycles that involve DNA replication and karyokinesis without cytokinesis (Unhavaithaya and Orr-Weaver, 2012; Von Stetina et al., 2018). The SPGs undergo these variant cell cycles to increase their size rapidly to sustain the growth of the underlying brain during larval development. The polyploidization of these cells plays an important role in maintaining their epithelial barrier function, although it remains unclear whether these cells continue to endocycle or endomitose in the adult.

Polyploidy can also confer an increased biosynthetic capacity to cells and resistance to DNA damage induced cell death (Edgar and Orr-Weaver, 2001; Lee et al., 2009; Mehrotra et al., 2008; Zhang et al., 2014). Several studies have noted neurons and glia in the adult fly brain with large nuclei (Robinow and White, 1991; Winberg et al., 1992) and in some cases neurons and glia of other insect species in the adult CNS are known to be polyploid (Nordlander and Edwards, 1969). Rare instances of neuronal polyploidy have been reported in vertebrates under normal conditions (Morillo et al., 2010) and even in the CNS of mammals (López-Sánchez and Frade, 2013; Shai et al., 2015).

Polyploidization is employed in response to tissue damage and helps maintain organ size (Cohen et al., 2018; Tamori and Deng, 2013; Losick et al., 2016; Losick et al., 2013). Therefore, polyploidy may be a strategy to deal with damage accumulated with age in the brain, a tissue with very limited cell division potential. Here we show that polyploid cells accumulate in the adult fly brain and that this proportion of polyploidy increases as the animals approach middle-age. We show that multiple types of neurons and glia which are diploid at eclosion which become polyploid specifically in the adult brain. We have found that the optic lobes of the brain contribute to most of the observed polyploidy. We also observe increased DNA damage with age, and show that inducing oxidative stress and exogenous DNA damage can lead to increased levels of polyploidy. We find that polyploid cells in the adult brain are resistant to DNA damage-induced cell death and propose a potentially protective role for polyploidy in neurons and glia in adult Drosophila melanogaster brains.

Cell ploidy often scales with cell size and biosynthetic capacity (Edgar and Orr-Weaver, 2001; Orr-Weaver, 2015). The brain is thought to be a notable exception to this rule, where the size of postmitotic diploid neurons and glia can be highly variable. We wondered whether alterations in ploidy during late development or early adulthood may contribute to the variability in neuronal and glial cell size in the mature Drosophila brain. We therefore developed a sensitive flow cytometry assay to measure DNA content in Drosophila pupal and adult brains. Briefly, this assay involves dissociating brains with a trypsin or collagenase based solution followed by quenching the dissociation and labeling DNA with DyeCycle Violet (Grushko and Buttitta, 2015) in the same tube, to avoid cell loss from washes. Samples are then immediately run live on a flow cytometer for analysis. We employed strict gating parameters to eliminate doublets (Figure 1—figure supplement 1; López-Sánchez et al., 2017b). This assay is sensitive enough to measure DNA content from small subsets of cells (e.g. Mz19-GFP expressing neurons) from individual pupal or adult brains (Figure 1—figure supplement 1D). Using this approach we confirmed that under normal culturing conditions, cell proliferation and DNA replication ceases in the pupal brain after 24 hr into metamorphosis (24 hr APF) (Figure 1—figure supplement 1E), and that only the previously described mushroom body neuroblasts continue to replicate their DNA and divide in late pupa (Siegrist et al., 2010). The brains of newly eclosed adult flies are 98–99% diploid and we, like others, only rarely observe EdU incorporation during the first week of adulthood in wild-type flies under normal conditions but not later in adulthood (Figure 1—figure supplement 1F; Fernández-Hernández et al., 2013; Foo et al., 2017; Kato et al., 2009; Siegrist et al., 2010; von Trotha et al., 2009). We were therefore surprised to find a distinct population of cells with DNA content of 4C and up to >16C appearing in brains of aged animals of various genotypes under normal culture conditions (Figure 1—figure supplement 1G).

Polyploid cells accumulate in the adult Drosophila brain

We performed a systematic time-course to measure accumulation of polyploid cells in the adult brain in isogenic w¹¹¹⁸ male and female flies cultured under standard conditions (Linford et al., 2013). We measured the percentage of polyploid cells in individual brains from the day of eclosion until 56 days (8 weeks) at weekly intervals. Polyploid cells appear as early as 7 days into adulthood, and the proportion of polyploidy continues to rise until animals are 21 days old (Figure 1A). This increase in polyploidy is only observed until week 3, after which the proportion of polyploid cells observed remains variable from animal to animal, but on average, does not increase. We observe similar patterns of polyploidy accumulation in males and females (Figure 1A). To ensure that the polyploidy we observe is not an artefact of one particular strain, we performed similar measurements across the lifespan in other commonly used lab ‘wild-type’ strains Canton-S (Figure 1B) and Oregon-R (Figure 1C). Interestingly, Oregon-R flies show lower levels of polyploidy in the first two weeks than w¹¹¹⁸ and Canton-S suggesting that different genetic backgrounds may influence polyploidy in the brain. We also performed DNA content measurements of brains from the distantly related D.americana which diverged ~50 million years ago and a more closely related species, D.mauritiana, which diverged ~2 million years ago (Figure 1C). While both species show accumulation of polyploidy, it is interesting to note that they show differences in levels of polyploidy.

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We next measured changes in ploidy in the D. melanogaster adult brain over time. We pooled data from multiple animals and binned polyploid cells from w¹¹¹⁸ brains into two categories: cells with 4C (tetraploid) DNA content measured by flow cytometry and cells with >4C DNA content - this includes 8C, 16C and even some 32 C cells (Figure 1D). The majority of the polyploid cells appear to be tetraploid, and the fraction of cells exhibiting >4C DNA content increases during the first week of adulthood, but remains relatively consistent with age.

We next asked whether polyploid cells are located in a specific region of the brain. We dissected the Drosophila central nervous system (CNS) into the central brain, optic lobes, and ventral nerve cord (VNC) and measured levels of polyploidy in each region from day of eclosion to 2 weeks into adulthood (Figure 1E). We found that while there is a low level of polyploidy in the central brain and VNC that increases with age, most of the polyploidy comes from the optic lobes. Strikingly, by 3 weeks, over 20% of the cells in the optic lobes can exhibit polyploidy.

Since the optic lobes contribute to most of the polyploidy observed, we wondered if this phenomenon may be dependent on light. Canton-S animals reared in complete darkness did not show difference in polyploidy compared to age-matched controls raised in regular 12 hr light/12 hr dark cycles (Figure 1—figure supplement 2A). Next, we hypothesized that polyploidy accumulation may depend on proper photoreceptor function. However, glass^60j flies devoid of photoreceptors and pigment cells in compound eyes (Helfrich-Förster et al., 2001) still show polyploidy (Figure 1—figure supplement 2B).

Multiple cell types exhibit adult-onset polyploidy in the brain

To identify which cell types in the brain are becoming polyploid, we used the binary GAL4/UAS system to drive the expression of a nuclear-localised green or red fluorescent protein (nGRP or nRFP) with cell type-specific drivers. We then measured DNA content using Dye-Cycle Violet in the GFP or RFP-positive populations.

We first examined the SPGs, as previous work from the Orr-Weaver lab identified these to be highly polyploid (Unhavaithaya and Orr-Weaver, 2012; Von Stetina et al., 2018). When we used the SPG driver moody-GAL4, we found that the SPGs are highly polyploid (Unhavaithaya and Orr-Weaver, 2012), but contributed to less than 5% the polyploid cells observed in mature adult brains (Figure 2—figure supplement 1A,C). Another class of cells previously shown to be polyploid in some contexts are tracheal cells that carry oxygen to tissues (Zhou et al., 2016). Using the tracheal driver breathless-GAL4, we found that in 10 day old adult brains, tracheal cells comprise less than 3% of all polyploid cells (Figure 2—figure supplement 1B,C). Thus, 90% of the polyploid cells we observe in the brain arise from cell types not previously known to become polyploid.

The adult fly brain is thought to be composed almost entirely of neurons (90% of total population) and glia (10% of total population). First, we asked if neurons become polyploid by using a pan-neuronal driver, nSyb-GAL4 to drive UAS-nGFP (Figure 2A). We found that indeed, by two weeks ~ 5–6% of cells expressing nSyb-GAL4 show >2C DNA content. Similarly, we used the pan-glial driver Repo-GAL4 and found that by 2 weeks ~ 6–7% of glia also become polyploid in the adult brain (Figure 2B). Neurons outnumber glial cells in the fly brain, and we find that the relative proportions of polyploid cells reflect the total ratio of neurons vs. glia in the adult brain (Figure 2C). We next asked whether specific types of neurons or glia show higher levels of polyploidy. We measured the proportion of polyploid vs diploid cells in various classes of neurons (Figure 2D) and glia (Figure 2E) in 7 day old optic lobes. Interestingly, we found that most differentiated cell types we assayed in the optic lobes show some level of polyploidy by one week of age. We conclude that polyploidy arises in multiple neuronal and glial types that are initially diploid upon eclosion and become polyploid after terminal differentiation and specifically during adulthood.

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Most of the polyploidy is not a result of cell fusion

We reasoned that cells in the brain could become polyploid either by re-entering the cell cycle or by undergoing cell fusion (Alvarez-Dolado and Martínez-Losa, 2011; Giordano-Santini et al., 2016; Grendler et al., 2019; Losick et al., 2013; Schoenfelder et al., 2014; Shu et al., 2018; Starnes et al., 2016). To examine whether cell fusion occurs, we used a genetic labeling tool called CoinFLP (Bosch et al., 2015). The CoinFLP genetic cassette contains two overlapping but exclusive Flippase Recombination Target (FRT) sites flanking a stop cassette that can be ‘flipped -out’ using FRT mediated recombination to give rise to cells expressing either a LexGAD driver or a GAL4 driver, which can be used to drive expression of lexA_op-GFP (green) and UAS-RFP (red). In animals heterozygous for CoinFLP, a diploid cell has only one copy of the transgenic cassette which can only be ‘flipped’ to give rise to a cell permanently labeled with either red or green fluorescent proteins, hence the name CoinFLP. If labeling is induced in the brain early during development before eclosion, cells become stochastically and permanently labeled with either red or green fluorescent proteins. If cells fuse in the ageing brain, up to ⅓ of cells undergoing fusion could fuse a red-labeled cell with a green cell and appear yellow. We used a FLP recombinase (flippase) under the control of the eyeless promoter (ey-FLP) to label most of the cells red or green in the optic lobes early in development (Figure 3A–B’) and did not observe any double labeled (yellow) cells in young adult brains or older brains. We also expressed flippase enzyme more broadly under the control of a heat-shock promoter (hs-FLP) and labeled cells using a nuclear GFP or RFP at larval L2-L3 stages (Figure 3C) and measured the number of double-labeled cells in the optic lobes at on the day of eclosion or after aging at 14 days post-eclosion. We never observed more than 10–12 cells per optic lobes exhibiting double-labeling under these ‘early-FLP’ conditions. These double-labeled cells under the larval hs-FLP conditions likely include the SPG cells which become polyploid early in larval development and do not express ey-FLP. We conclude that very little cell fusion occurs in the adult OL, even with age.

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‘Late-FLP’ can label polyploid cells that arise from cell cycle reentry

By using a modified labeling paradigm, we can also use CoinFLP to label polyploid cells in situ (Figure 4A). Previous work with CoinFLP has shown that inducing ‘flipping’ in cells that are already polyploid results in a fraction of double labeled yellow cells (Bosch et al., 2015). We therefore reasoned that heterozygous CoinFLP brain cells that become polyploid by replicating their genome during adulthood will contain two or more copies of the CoinFLP transgene cassette. If we label cells by activating hs-FLP late in adulthood after polyploidy appears, some polyploid cells may ‘flip’ one copy green and one copy red, appearing yellow. When we induce an adult FLP at one day, before polyploidy occurs, we do not observe any double-labeled cells in the optic lobe (Figure 4B) but when we induce an adult FLP at 30 days post-eclosion, we observe several double labeled cells (Figure 4B’) indicating that these cells have undergone genome replication and contain at least two heterozygous copies of the CoinFLP transgenic cassette. To quantify this, we used an adult ‘late-FLP’ to drive nuclear GFP and RFP, and we observe around 300 double-labeled cells per optic lobes in 14 day old brains (Figure 4C). The presence of double-labelled nuclei in aged optic lobes suggest cells become polyploid by cell cycle re-entry and endoreduplicating DNA.

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We further confirmed that the double-labeled cells visualized by microscopy are polyploid by performing DAPI intensity quantification in high-magnification images (Figure 4—figure supplement 1) and flow cytometry. (Figure 4—figure supplement 2). All CoinFLP double-labeled cells were confirmed to be polyploid by DAPI integrated intensity measurements and 97% of all double-labeled cells show >2C DNA content by FACS (Figure 4—figure supplement 2). CoinFLP double-labeling confirmed several types of glia identifiable by location and shape to become polyploid, such as a subset of cortex glia of the outer (Figure 4D) and inner (Figure 4E) optic chiasm and astrocyte-like glia (Figure 4F) in the medulla of the OL.

To test whether polyploidy in the adult optic lobes is driven by cell cycle re-entry, we used cell-type specific RNA-interference (RNAi) to modulate the DNA replication licensing factors cdc6 and Geminin in postmitotic neurons. Cdc6 is an essential factor for DNA replication licensing that promotes the recruitment of the MCM complex to load the DNA replication complex (Kang et al., 2014), while Geminin is a replication licensing inhibitor that sequesters DNA replication licensing factors to inhibit DNA re-replication (Lutzmann et al., 2006). Using nSyb-GAL4, we expressed UAS-cdc6^RNAi in differentiated neurons which significantly reduced levels of polyploidy by 14d (Figure 4G) from ~25% in control optic lobes to ~14% on optic lobes expressing the RNAi. We next knocked down geminin and found that we increase levels of polyploidy in the optic lobes (Figure 4G). This suggests that a fraction of post-mitotic neurons reactivate DNA replication to become polyploid in the adult fly brain.

DNA damage accumulates in adult optic lobes

To investigate whether transcriptional changes that occur with age may be associated with cell cycle reactivation and polyploidy in the brain, we performed RNA sequencing on three parts of the CNS: optic lobes, central brain and VNC from male and female Canton-S animals at different time points: 1 day, 2 days, 7 days and 21 days post-eclosion. To infer biological processes that are affected with age, gene ontology analysis was performed using GOrilla and redundant terms were filtered using reviGO. The most significant changes observed in the optic lobes at 21d compared to 2d are shown in Figure 5A,B. Among the most significantly upregulated groups of genes are those associated with the cell cycle, DNA damage response and DNA damage repair. The enrichment of up-regulated genes associated with the DNA damage response was also observed in the optic lobes at 7 days (Figure 5—figure supplement 1), but the enrichment and fold-induction of specific genes is stronger at day 21 (Figure 5A). A gene expression signature associated with DNA damage is specific to the optic lobes. However, the most significantly downregulated GO terms in the optic lobes at 21d are shared with the central brain and VNC and include metabolism, transmembrane transport and cellular respiration-associated processes (Figure 5—figure supplement 1).

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To examine whether DNA damage is higher in the OL, we performed immunostaining against the phosphorylated histone 2A variant (pH2AV) in 1d optic lobes and central brain and 21d optic lobes and central brain (Figure 5C–E) from Canton-S male brains. Young brains show very low levels of pH2AV in both the optic lobes and central brain (Figure 5C,C’,E) but older brains show higher levels of pH2AV in the optic lobes compared to the central brain (Figure 5D,D’,E).

To further understand the DNA damage and cell cycle signatures observed with age, we looked at the change in expression of specific genes involved in the DNA damage response and the cell cycle (Figure 5F). Recent work has identified a specific transcriptional response to induced DNA damage in the head that involved a non-canonical role for tumor suppressor protein p53 (Kurtz et al., 2019). This signature was termed head Radiation Induced p53-Dependent or hRIPD. In addition to genes such as FANCI, loki, rad50 and xrp1 which are involved in a canonical, ionising radiation-induced DNA damage response, we also find robust upregulation of hRIPD genes Ku80, Irbp, Cht8, CG3344 and CG4734 in our RNAseq data set at 7d and 21d in optic lobes. However, these genes are not as strongly upregulated in the aged central brain or VNC and p53 itself shows only a small increase in the optic lobes at 21d (Figure 5F). Consistent with cell cycle re-entry in a fraction of cells in the OL, upregulation of cell cycle genes such as myc, cyclin D, orc1 is observed specifically in the optic lobes and increases with age.

Polyploidy accumulation in neurons is p53-independent

Work in other polyploid tissues in Drosophila has shown that polyploid cells in the salivary gland can tolerate high levels of DNA double-strand breaks and resist apoptosis caused by DNA damage (Hassel et al., 2014; Mehrotra et al., 2008; Qi and Calvi, 2016; Zhang et al., 2014). This is possible because polyploid cells in tissues such as the salivary gland have intrinsically low levels of p53 protein and also suppress the expression of pro-apoptotic genes (Zhang et al., 2014). It has also been shown in various tissues and organisms that DNA damage can induce polyploidization (Bretscher and Fox, 2016; Donovan and Corbo, 2012; Grendler et al., 2019). Since we observe a modest upregulation of p53 as well as a p53-dependent gene expression signature in older optic lobes, we asked if the induction of polyploidy in neurons is p53 dependent. To address this, we overexpressed wildtype (p53^WT) or a dominant-negative allele of p53 (p53^DN) that is unable to bind to DNA and evoke a transcriptional response in neurons using the nSyb-GAL4 driver (Figure 6A). We did not see a significant difference in levels of polyploidy in 7 day old brains with overexpression of either WT or mutant p53, suggesting that accumulation of polyploidy in neurons is p53-independent. We also performed cell death measurement in the brain using flow cytometry. We calculated cell death by measuring proportions of cells incorporating either Propidium Iodide (PI) or Sytox-Green (Figure 6—figure supplement 1). We did not see a significant difference in the proportion of dead cells in overexpression of p53^WT or p53^DN conditions compared to control (Figure 6—figure supplement 1B) consistent with recent work suggesting a non-canonical, non-apoptotic role for p53 in the adult Drosophila brain (Kurtz et al., 2019).

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Author details

1. Shyama Nandakumar

   Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0624-3452

2. Olga Grushko

   Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States

   Contribution

   Conceptualization, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

3. Laura A Buttitta

   Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States

   Contribution

   Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Investigation, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   buttitta@umich.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5064-0650

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