A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium

Abstract

Commitment to and completion of sexual development are essential for malaria parasites (protists of the genus Plasmodium) to be transmitted through mosquitoes1. The molecular mechanism(s) responsible for commitment have been hitherto unknown. Here we show that PBAP2-G, a conserved member of the ApiAP2 family of transcription factors, is essential for the commitment of asexually replicating forms to sexual development in P. berghei, a malaria parasite of rodents. PBAP2-G was identified from mutations in its encoding gene, PBANKA_143750, which account for the loss of sexual development frequently observed in parasites transmitted artificially by blood passage. Systematic gene deletion of conserved ApiAP2 genes in Plasmodium confirmed the role of PBAP2-G and revealed a second ApiAP2 member (PBANKA_103430, termed PBAP2-G2) that significantly modulates but does not abolish gametocytogenesis indicating that a cascade of ApiAP2 proteins are involved in commitment to the production and maturation of gametocytes. The data suggest a mechanism of commitment to gametocytogenesis in Plasmodium consistent with a positive feedback loop involving PBAP2G which might be exploited to prevent the transmission of this pernicious parasite.

Global transcriptional repression: An initial and essential step for Plasmodium sexual development

“…These results indicated that the disruption of AP2-G2 did not abrogate sexual commitment or sex determination but did cause marked developmental defects in the gametocytes, together with a marked reduction of sex-specific gene expression. The phenotypes of the AP2-G2(−)820 parasites obtained in the present study and those reported by Sinha et al were largely similar; i.e., only a small proportion of mature gametocytes was observed in the AP2-G2(−)820 parasites (8). However, the present study showed that despite being indistinguishable from trophozoites, gametocytes were present in the AP2-G2(-)820 parasites as in the original parasites.…”

“…Thus, there is a long intervening period between the completion of sexual commitment and the onset of sexual differentiation as well as between the expression of the two transcription factors that are associated with these events. If AP2-G2 is downstream in a transcriptional cascade initiated with AP2-G as suggested (8), it may be that the expression of AP2-G2 is silenced at a posttranscriptional level during this interval. At present, however, in vivo evidence for the events occurring during this period is still lacking, and further studies are required to elucidate the relationships between these two transcription factors in gametocytogenesis.…”

“…During this analysis, we found that one P. berghei AP2 family transcription factor (PlasmoDB gene ID: PBANKA_103430, later designated as AP2-G2) was expressed in both male and female gametocytes (8). We further investigated the expression profile and the role of this transcription factor in gametocytogenesis, and we report that AP2-G2 is a transcription factor that may induce genome-wide gene repression in the initial phase of gametocyte development.…”

“…Recently, two AP2 family transcription factors, AP2-G and AP2-G2, have been reported to be involved in gene regulation required for gametocytogenesis. AP2-G disruptants completely lack gametocytes (7,8), indicating that this transcription factor acts as a switch for commitment to sexual development. AP2-G2 disruptants almost completely lack mature gametocytes (8), suggesting that this transcription factor plays a critical role in the production and maturation of gametocytes.…”

“…AP2-G disruptants completely lack gametocytes (7,8), indicating that this transcription factor acts as a switch for commitment to sexual development. AP2-G2 disruptants almost completely lack mature gametocytes (8), suggesting that this transcription factor plays a critical role in the production and maturation of gametocytes. These studies suggest that gametocytogenesis in malaria parasites is regulated by a cascade of AP2 family transcription factors starting with AP2-G.…”