Regulatory principles governing the maternal-to-zygotic transition: insights from Drosophila melanogaster

Abstract

The onset of metazoan development requires that two terminally differentiated germ cells, a sperm and an oocyte, become reprogrammed to the totipotent embryo, which can subsequently give rise to all the cell types of the adult organism. In nearly all animals, maternal gene products regulate the initial events of embryogenesis while the zygotic genome remains transcriptionally silent. Developmental control is then passed from mother to zygote through a process known as the maternal-to-zygotic transition (MZT). The MZT comprises an intimately connected set of molecular events that mediate degradation of maternally deposited mRNAs and transcriptional activation of the zygotic genome. This essential developmental transition is conserved among metazoans but is perhaps best understood in the fruit fly, Drosophila melanogaster. In this article, we will review our understanding of the events that drive the MZT in Drosophila embryos and highlight parallel mechanisms driving this transition in other animals.

Keywords: Drosophila; Zelda; cellular reprogramming; embryogenesis; maternal-to-zygotic transition; zygotic genome activation.

Figure 1.

The interplay between maternal clearance and zygotic genome activation during the MZT in Drosophila. (a) Model of maternal and zygotic gene expression dynamics over the MZT. Maternal mRNA stores are eliminated through the action of two RNA degradation pathways: an ‘early decay’ pathway driven by maternally contributed factors following egg activation, independent of zygotic transcription; and a ‘late decay’ pathway directed by zygotically expressed factors. Zygotic genome activation (ZGA) occurs gradually over the MZT, with early onset expression of about one hundred zygotic genes (minor ZGA) appearing several nuclear cycles (nc) before the subsequent widespread activation of the zygotic genome (major ZGA). (b) Maternally loaded RNAs and proteins translated from these RNAs (blue) regulate molecular events governing the MZT, including mitotic division-cycle dynamics, maternal mRNA turnover and zygotic genome activation. Products of zygotic transcription (red), in turn, contribute to division-cycle remodelling and maternal RNA destabilization.

Figure 2.

Multiple mechanisms trigger the onset of division-cycle remodelling and zygotic transcription. (a) The early embryo exists as a syncytium of nuclei undergoing rapid division cycles of repeated DNA replication (S) and mitosis (M). Progressive elongation of S-phase permits time to achieve transcriptional competence from the zygotic genome. The major wave of genome activation occurs at the onset of cycle 14, accompanied by cellularization of nuclei and the introduction of a gap phase (G2). (b) A proposed maternally supplied repressor (red) inhibits transcription in the early embryo. As the number of nuclei increases exponentially with each division, the nuclear : cytoplasmic ratio increases, titrating away the repressor and allowing zygotic transcription to initiate. (c) Maternal clock model in which translation of a maternal activator (green) requires a set amount of developmental time following fertilization to accumulate sufficient levels of protein to trigger ZGA.

Figure 3.

Dynamic changes in the chromatin landscape correlate with zygotic genome activation. (a) Schematic of staged embryos at nuclear cycles spanning early, mid and late MZT. (b) Maternal ZLD is required to maintain regions of open chromatin near early expressed zygotic genes. Later, during the major wave of ZGA, both binding sites for ZLD (green) and GA-di-nucleotide binding proteins (purple) are enriched at accessible regions of the genome. (c) Embryonic linker histone variant, dBigH1, is abundant in the early embryo when the genome is inactive. During cycles 13–14, coinciding with the major wave of ZGA, dBigH1 is replaced with somatic H1. (d) As the MZT progresses, there is an overall increase in histone modifications incorporated into the zygotic genome. H4K5ac is highest during early nuclear cycles associated with rapid DNA replication. At cycles 8–12, histone acetylation marks (blue) are enriched near loci activated during the minor wave of ZGA. During cycles 13–14, there is an increase in both histone methylation marks associated with active (green) and repressive (red) transcription. (e) Progressive demarcation of topologically associated domain (TAD) boundaries, as determined by Hi-C data, occurs over the MZT concomitant with ZGA.