Chemical reactions form the foundation of life, yet such elementary activities are rarely considered when trying to understand higher-level processes, such as embryonic development. Nevertheless, as recently shown by Artieri and Fraser (MBE 2014), limitations on the kinetics of gene expression strongly constrain the length of highly expressed transcripts during early embryonic development of fruit flies. Furthermore, this phenomenon appears to be a general feature of fruit fly development as it is evolutionarily conserved across a number of species.
The long and short of mRNA transcription
It has long been known that only a portion of the mRNA molecules are used to produce functional proteins – multicellular species contain many long ‘introns’, which must first be transcribed, then spliced out before translation can occur. Introns can be very long, causing transcription of some mRNA molecules to take significant amounts of time: for example, one 2.3 million bp transcript in humans takes over half a day to be produced. This creates a problem as incompletely transcribed mRNA molecules are degraded when DNA is replicated at the beginning of cell division, and the process must begin anew once division is completed. Together, this implies that cell divisions need to be spaced out long enough apart from each other to produce all of the transcripts necessary for the growth of the cell before the next division occurs.
Studies of fruit fly development have shown that zygotes undergo “syncytial division” at the beginning of development, where the DNA within the zygotic nuclei divide every ~10 minutes for 9 cycles, followed by 4 additional progressively lengthening divisions. While most mRNA in the cell at this time are supplied by the mother (maternal mRNA), this also represents the phase during which the zygote begins producing its own mRNA. The extremely rapid cell divisions led Artieri and Fraser to hypothesize that long mRNA molecules transcribed from the zygotic genome may be underrepresented during these early stages of development. Maternal mRNAs, on the other hand, would be unaffected as they are already present in the cell and do not have to be transcribed.
Transcript length vs. developmental timing
The authors classified embryonically expressed genes as “maternal” or “zygotic” depending on whether or not the gene was present as maternal mRNA in unfertilized embryos using published data. They then obtained multiple developmental mRNA expression timecourses and found that long zygotically expressed genes took longer to reach maximal expression levels than short genes – consistent with their inability to be fully transcribed during early development (Figure 1). Furthermore, they were able to use total RNA expression data to detect the presence of incomplete transcripts, indicating that delay was not due to later transcriptional activation, but rather the incomplete production of transcripts.Using a published set of developmental mRNA expression timecourses from additional Drosophila species, Artieri and Fraser show that these patterns are consistent across all species examined. Finally, they also observed that the introns present in highly expressed zygotic genes appear to be highly evolutionarily constrained in terms of their lengths when compared to either genes maternally deposited or zygotically expressed during later timepoints. This suggests that natural selection has played a role in limiting the expansion of introns in early expressed zygotic genes, allowing them to escape ‘intron delay’.
In summary, Artieri and Fraser have found evidence that a significant fraction of zygotically expressed transcripts in fruit flies are delayed from reaching their maximal levels of expression due to the rapid cell cycles taking place at the beginning of development. This suggests a simple mechanism for developmental timing of zygotic gene expression: genes that are required early must be short, while genes whose expression is needed at a later time can delay their expression via the presence of long introns. While some evidence for the use of intron length as a regulatory mechanism has recently emerged (Takashima et al. 2011), future experiments will be required to determine how widespread is the effect of selection to maintain long lengths and delayed expression.
Carlo G. Artieri and Hunter B. Fraser Transcript Length Mediates Developmental Timing of Gene Expression Across Drosophila. (2014) Molecular Biology and Evolution doi:10.1093/molbev/msu226
Takashima Y, Ohtsuka T, González A, Miyachi H, Kageyama R. Intronic delay is essential for oscillatory expression in the segmentation clock. Proc Natl Acad Sci U S A. 2011;108:3300-3305.