Regulators of male and female sexual development are critical for the transmission of a malaria parasite

Russell, Andrew J.; Sanderson, Theo; Bushell, Ellen; Talman, Arthur M.; Anar, Burçu; Girling, Gareth; Hunziker, Mirjam; Kent, Robyn S; Martin, Julie S.; Metcalf, Tom; Montandon, Ruddy; Pandey, Vikash; Pardo, Mercedes; Roberts, A.; Sayers, Claire P.; Schwach, Frank; Choudhary, Jyoti; Rayner, Julian C.; Voet, Thierry; Modrzynska, Katarzyna; Waters, Andrew P.; Lawniczak, Mara K. N.; Billker, Oliver

doi:10.1016/j.chom.2022.12.011

Cited by 33 publications

(45 citation statements)

References 72 publications

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“…All predefined morphotypes (A to E) have been detected over time in vitro , including type E meronts, which are expected to mature into sexual gametes 3 . However, fully differentiated microgametocytes and macrogametocytes were not observed probably because gamete formation requires a complex genetic program as in Plasmodium falciparum 38, 39 or a dedicated metabolic environment found exclusively in feline enterocytes 40 .…”

Section: Discussionmentioning

confidence: 99%

In vitroproduction of cat-restrictedToxoplasmapre-sexual stages by epigenetic reprogramming

Antunes

Shahinas

Swale

et al. 2023

Preprint

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Summary paragraphSexual reproduction ofToxoplasma gondii, which is restricted to the small intestine of felids, is sparsely documented, due to ethical concerns surrounding the use of cats as model organisms. Chromatin modifiers dictate the developmental fate of the parasite during its multistage life cycle, but their targeting to stage-specific cistromes is poorly described1. In this study, we found that transcription factors AP2XII-1 and AP2XI-2, expressed in tachyzoite stage that causes acute toxoplasmosis, can silence genes necessary for merozoites, a developmental stage critical for sexual commitment and transmission to the next host, including humans. Their conditional and simultaneous depletion leads to a drastic change in the transcriptional program, promoting a complete transition from tachyzoites to merozoites. Pre-gametes producedin vitrounder these conditions are characterized by specific protein markers and undergo typical asexual endopolygenic division cycles. In tachyzoites, AP2XII-1 and AP2XI-2 bind DNA as heterodimers at merozoite promoters and recruit the epigenitors MORC and HDAC31, which in turn restrict the accessibility of chromatin to the transcriptional machinery. Thus, the commitment to merogony stems from a profound epigenetic rewiring orchestrated by AP2XII-1 and AP2XI-2. This effectivein vitroculture of merozoites paves the way to exploreToxoplasmasexual reproduction without the need to infect kittens and has potential for the development of therapeutics to block parasite transmission.

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Section: Discussionmentioning

confidence: 99%

In vitroproduction of cat-restrictedToxoplasmapre-sexual stages by epigenetic reprogramming

Antunes

Shahinas

Swale

et al. 2023

Preprint

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“…PbAP2R-2 is expressed in females, and pbap2r-2 knockout parasites [pbap2r-2(-)] are not able to form banana-shaped ookinetes [20]. Furthermore, in the recent study by Russell et al, pbap2r-2 was identified as one of the genes critical for female differentiation (referred as fd3) [45]. Therefore, we hypothesized that PbAP2R-2 might play an essential role in female development and assessed its function.…”

Section: Pbap2-fg2 Requires a Co-repressor Pbap2r-2 To Repress Its Ta...mentioning

confidence: 99%

“…Therefore, we proposed that the repressor complex repressed a subset of male genes that include those essential for regulating male differentiation. Very recently, Russel et al identified five genes that are essential for male differentiation [45], but these genes were not included in the target gene list of PbAP2-FG2 and PbAP2R-2. Collectively, we concluded that the PbAP2-FG2-PbAP2R-2 complex could play three roles: promoting female differentiation by repressing early gametocyte genes, modulating the expression level of female genes, and suppressing male differentiation.…”

Section: Plos Pathogensmentioning

confidence: 99%

PbAP2-FG2 and PbAP2R-2 function together as a transcriptional repressor complex essential for Plasmodium female development

2023

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Gametocyte development is a critical step in the life cycle of Plasmodium. Despite the number of studies on gametocyte development that have been conducted, the molecular mechanisms regulating this process remain to be fully understood. This study investigates the functional roles of two female-specific transcriptional regulators, PbAP2-FG2 and PbAP2R-2, in P. berghei. Knockout of pbp2-fg2 or pbap2r-2 impairs female gametocyte development, resulting in developmental arrest during ookinete development. ChIP-seq analyses of these two factors indicated their colocalization on the genome, suggesting that they function as a complex. These analyses also revealed that their target genes contained a variety of genes, including both male and female-enriched genes. Moreover, differential expression analyses showed that these target genes were upregulated through the disruption of pbp2-fg2 or pbap2r-2, indicating that these two factors function as a transcriptional repressor complex in female gametocytes. Formation of a complex between PbAP2-FG2 and PbAP2R-2 was confirmed by RIME, a method that combines ChIP and MS analysis. In addition, the analysis identified a chromatin regulator PbMORC as an interaction partner of PbAP2-FG2. Comparative target analysis between PbAP2-FG2 and PbAP2-G demonstrated a significant overlap between their target genes, suggesting that repression of early gametocyte genes activated by PbAP2-G is one of the key roles for this female transcriptional repressor complex. Our results indicate that the PbAP2-FG2-PbAP2R-2 complex-mediated repression of the target genes supports the female differentiation from early gametocytes.

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“…Six putative dynein motor-associated genes, dhc6 (dynein heavy chain, PY17X_0603800), dhc7 (dynein heavy chain, PY17X_0510800), dlc1 (dynein light chain, PY17X_1241500), dlc2 (dynein light chain, PY17X_0302800), drc1 (dynein regulatory complex protein, PY17X_0721100), and dbc (dynein beta chain, PY17X_1333900), were included. The md2 (male development protein 2, PY17X_1450400), a potential male determining gene recently identified [39], was also included. The rest 17 IR genes had not been previously described in the Plasmodium .…”

Section: Resultsmentioning

confidence: 99%

“…During the manuscript preparation of this study, another work by Russell et al . [39] demonstrated that gene deletion of the Rbpm1 ortholog (PBANKA_0716500, named as md5 ) had no effect on female and male gametocyte formation, but resulted in male-specific infertility in the P. berghei . These findings are consistent with the male gamete formation deficiency phenotype of the ΔRbpm1 in P. yoelii in this study, indicating conserved function of RBPm1 in the rodent malaria parasites.…”

Section: Discussionmentioning

confidence: 99%

An axonemal intron splicing program sustainsPlasmodiummale development

Guan,

Wu,

et al. 2023

Preprint

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Differentiation of male gametocyte into flagellated fertile male gamete relies on the axoneme assembly, a major component of male development for mosquito transmission of malaria parasite. RNA-binding protein (RBP)-mediated post-transcription regulation plays important roles in eukaryotic sexual development, including thePlasmodiumfemale development. However, the role of RBP in defining thePlasmodiummale transcriptome and its function in the male gametogenesis remain elusive. Here, we screened the gender expression of the genome-wide RBPs and identified an undescribed male-specific RBP geneRbpm1in thePlasmodium. RBPm1 is localized in the nucleus of male gametocytes. RBPm1-deficient parasites fail to assemble the axoneme for male gametogenesis and thus mosquito transmission. RBPm1 interacts with spliceosome E complex and regulates splicing initiation of certain introns in a group of 26 axonemal genes. RBPm1 deficiency results in intron retention and protein loss of these axonemal genes. Intron deletion restores axonemal proteins expression and partially rectifies axonemal defects in RBPm1-null gametocytes. Further splicing assays in both reporter and endogenous genes exhibit stringent recognition of the axonemal introns by RBPm1. Therefore, the splicing activator RBPm1 and its target introns constitute an axonemal intron splicing program in the post-transcription regulation essential forPlasmodiummale development.

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Regulators of male and female sexual development are critical for the transmission of a malaria parasite

Cited by 33 publications

References 72 publications

In vitroproduction of cat-restrictedToxoplasmapre-sexual stages by epigenetic reprogramming

In vitroproduction of cat-restrictedToxoplasmapre-sexual stages by epigenetic reprogramming

PbAP2-FG2 and PbAP2R-2 function together as a transcriptional repressor complex essential for Plasmodium female development

An axonemal intron splicing program sustainsPlasmodiummale development

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