In nearly all metazoans, the earliest stages of development are controlled by 
maternally deposited mRNAs and proteins. The zygotic genome becomes 
transcriptionally active hours after fertilization. Transcriptional activation 
during this maternal-to-zygotic transition (MZT) is tightly coordinated with the 
degradation of maternally provided mRNAs. In Drosophila melanogaster, the 
transcription factor Zelda plays an essential role in widespread activation of 
the zygotic genome. While Zelda expression is required both maternally and 
zygotically, the mechanisms by which it functions to remodel the embryonic 
genome and prepare the embryo for development remain unclear. Using 
Cas9-mediated genome editing to generate targeted mutations in the endogenous 
zelda locus, we determined the functional relevance of protein domains conserved 
amongst Zelda orthologs. We showed that neither a conserved N-terminal zinc 
finger nor an acidic patch were required for activity. Similarly, a previously 
identified splice isoform of zelda is dispensable for viability. By contrast, we 
identified a highly conserved zinc-finger domain that is essential for the 
maternal, but not zygotic functions of Zelda. Animals homozygous for mutations 
in this domain survived to adulthood, but embryos inheriting these 
loss-of-function alleles from their mothers died late in embryogenesis. These 
mutations did not interfere with the capacity of Zelda to activate transcription 
in cell culture. Unexpectedly, these mutations generated a hyperactive form of 
the protein and enhanced Zelda-dependent gene expression. These data have 
defined a protein domain critical for controlling Zelda activity during the MZT, 
but dispensable for its roles later in development, for the first time 
separating the maternal and zygotic requirements for Zelda. This demonstrates 
that highly regulated levels of Zelda activity are required for establishing the 
developmental program during the MZT. We propose that tightly regulated gene 
expression is essential to navigate the MZT and that failure to precisely 
execute this developmental program leads to embryonic lethality.