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The Mother-to-Child Transition

2007; Elsevier BV; Volume: 12; Issue: 6 Linguagem: Inglês

10.1016/j.devcel.2007.05.009

1878-1551

Wael Tadros, J. Timothy Westwood, Howard D. Lipshitz,

Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

Recent genome-scale analyses have uncovered the magnitude of the changes in mRNA populations that occur during the maternal-to-zygotic transition in early Drosophila embryos as well as two of the key regulators of this process, SMAUG and bicoid stability factor (BSF). Recent genome-scale analyses have uncovered the magnitude of the changes in mRNA populations that occur during the maternal-to-zygotic transition in early Drosophila embryos as well as two of the key regulators of this process, SMAUG and bicoid stability factor (BSF). The father's genes are largely irrelevant for early animal development. Instead, during a period that can range from a few hours (e.g., in Drosophila) to a couple of days (e.g., in humans) after fertilization, maternal gene products control development. These RNAs and proteins are loaded into the egg during oogenesis. Two processes subsequently drive the maternal-to-zygotic transition (MZT) during which developmental control is transferred to the zygotic genome: first, a subset of the maternal mRNAs is degraded; second, the zygotic genome is transcriptionally activated. In Drosophila, the first developmental event that requires the function of the zygotic genome is the process of blastoderm cellularization (Merrill et al., 1988Merrill P.T. Sweeton D. Wieschaus E. Development. 1988; 104: 495-509PubMed Google Scholar, Poulson, 1937Poulson D.F. Proc. Natl. Acad. Sci. USA. 1937; 23: 133-137Crossref Google Scholar, Wieschaus and Sweeton, 1988Wieschaus E. Sweeton D. Development. 1988; 104: 483-493Google Scholar), which occurs between 2.5 and 3.0 hr after fertilization. This developmental event, therefore, represents completion of the MZT and is known as the midblastula transition (MBT). Recent genome-scale studies have shed new light on the magnitude, timing, and regulation of the MZT in Drosophila. The magnitude of the mother's contribution to early development is surprisingly large: transcripts representing at least 50% of the entire protein-coding capacity of the genome—between 6,500 and 7,700 distinct mRNAs—are loaded into the egg and are present in the early embryo (De Renzis et al., 2007De Renzis S. Elemento O. Tavazoie S. Wieschaus E.F. PLoS Biol. 2007; 5: e117Crossref PubMed Scopus (187) Google Scholar, Tadros et al., 2007Tadros W. Goldman A.L. Babak T. Menzies F. Vardy L. Orr-Weaver T. Hughes T.R. Westwood J.T. Smibert C.A. Lipshitz H.D. Dev. Cell. 2007; 12: 143-155Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar). These are not just "housekeeping" mRNAs; many encode instructive proteins that regulate the cell cycle, signaling, and transcription of the zygotic genome itself. A significant fraction of these maternal mRNAs is eliminated during the MZT. Quantifying this fraction can be difficult. An unstable maternal mRNA can appear stable if its loss is compensated for by zygotic transcription (Figure 1A, compare the left and right panels). One solution to this problem is to use activated but unfertilized eggs. These are transcriptionally silent; thus, a transcript either remains unchanged (i.e., is stable) or decreases in amount (i.e., is unstable). Such analyses led to the conclusion that over 20% of the maternal mRNAs, representing about 1,600 distinct species, are degraded (Tadros et al., 2007Tadros W. Goldman A.L. Babak T. Menzies F. Vardy L. Orr-Weaver T. Hughes T.R. Westwood J.T. Smibert C.A. Lipshitz H.D. Dev. Cell. 2007; 12: 143-155Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar). This is an underestimate because a second and more efficient degradation machinery, which depends on zygotic transcription, is present in embryos (Figure 1C) but not in unfertilized eggs (Bashirullah et al., 1999Bashirullah A. Halsell S.R. Cooperstock R.L. Kloc M. Karaiskakis A. Fisher W.W. Fu W. Hamilton J.K. Etkin L.D. Lipshitz H.D. EMBO J. 1999; 18: 2610-2620Crossref PubMed Scopus (163) Google Scholar). Recently, De Renzis et al., 2007De Renzis S. Elemento O. Tavazoie S. Wieschaus E.F. PLoS Biol. 2007; 5: e117Crossref PubMed Scopus (187) Google Scholar cleverly teased apart the maternal versus zygotic contributions to each mRNA present at the MBT by using compound chromosomes to produce embryos lacking either a defined chromosome arm or even an entire chromosome. This method had been used previously to define the MBT (Merrill et al., 1988Merrill P.T. Sweeton D. Wieschaus E. Development. 1988; 104: 495-509PubMed Google Scholar, Wieschaus and Sweeton, 1988Wieschaus E. Sweeton D. Development. 1988; 104: 483-493Google Scholar). De Renzis et al. then measured the mRNA ratio between wild-type and chromosomally deficient embryos at the MBT. As expected, this ratio dropped significantly below 1.0 for a large fraction of transcripts since the vast majority of these mapped to the absent chromosome. For any individual gene, the extent of this drop was used to infer its zygotic contribution at the MBT while the residual signal indicated its maternal contribution. This approach revealed that 18% (1,158) of the transcripts expressed at the MBT have a significant zygotic component (Figure 1, blue curves). Not all of the measured effects were direct. In fact, the levels of 778 transcripts changed upon removal of a chromosome that did not harbor their corresponding gene. Twenty-eight percent of these secondary targets were zygotically derived, implying that the change in their expression levels occurs via effects on transcription, consistent with the fact that the set of 1,158 zygotic transcripts is highly enriched for gene ontology terms associated with transcriptional activity. Most of the remaining 72% of secondary targets are maternally supplied. Therefore, changes in their levels occur via altered stability. These are precisely the mRNAs whose stability is expected to be targeted by the "zygotic" degradation pathway alluded to earlier (Figure 1C), which is activated shortly before the MBT (Bashirullah et al., 1999Bashirullah A. Halsell S.R. Cooperstock R.L. Kloc M. Karaiskakis A. Fisher W.W. Fu W. Hamilton J.K. Etkin L.D. Lipshitz H.D. EMBO J. 1999; 18: 2610-2620Crossref PubMed Scopus (163) Google Scholar). Thus, 33% of maternally deposited mRNAs are degraded in embryos (De Renzis et al., 2007De Renzis S. Elemento O. Tavazoie S. Wieschaus E.F. PLoS Biol. 2007; 5: e117Crossref PubMed Scopus (187) Google Scholar) while only 21% are destabilized after activation of unfertilized eggs (Tadros et al., 2007Tadros W. Goldman A.L. Babak T. Menzies F. Vardy L. Orr-Weaver T. Hughes T.R. Westwood J.T. Smibert C.A. Lipshitz H.D. Dev. Cell. 2007; 12: 143-155Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar). Unexpectedly, the "zygotic" degradation activity maps to different chromosomes for different unstable maternal transcripts, implying that there are multiple independent degradation pathways. Why are two thirds of zygotically expressed transcripts also loaded into the egg maternally (Figure 1A and B, left panels)? De Renzis and colleagues present data consistent with the hypothesis that zygotic expression of an mRNA in a discrete pattern may confer a spatial component to the distribution of its encoded protein that cannot be accomplished by its more ubiquitously distributed (or, at least, less finely localized) maternal mRNA (De Renzis et al., 2007De Renzis S. Elemento O. Tavazoie S. Wieschaus E.F. PLoS Biol. 2007; 5: e117Crossref PubMed Scopus (187) Google Scholar). Computational analyses have enabled the identification of sequence elements that are enriched in the 3′UTRs of maternal transcripts as well as in the regulatory regions upstream of zygotic genes (De Renzis et al., 2007De Renzis S. Elemento O. Tavazoie S. Wieschaus E.F. PLoS Biol. 2007; 5: e117Crossref PubMed Scopus (187) Google Scholar, Tadros et al., 2007Tadros W. Goldman A.L. Babak T. Menzies F. Vardy L. Orr-Weaver T. Hughes T.R. Westwood J.T. Smibert C.A. Lipshitz H.D. Dev. Cell. 2007; 12: 143-155Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar). The 3′UTRs of maternal mRNAs are enriched for micro-RNA (miRNA) target sites and stem-loop structures known as SMAUG response elements, while those of unstable maternal transcripts are further enriched for two types of primary-sequence elements: PUF-domain protein binding sites and AU-rich elements (AREs). miRNAs, SMAUG, PUF proteins, and ARE-binding proteins are known regulators of RNA stability and translation. Zygotically transcribed genes are enriched for a heptamer (CAGGTAG, also independently identified by ten Bosch et al., 2006ten Bosch J.R. Benavides J.A. Cline T.W. Development. 2006; 133: 1967-1977Crossref PubMed Scopus (117) Google Scholar) in their upstream regulatory regions (De Renzis et al., 2007De Renzis S. Elemento O. Tavazoie S. Wieschaus E.F. PLoS Biol. 2007; 5: e117Crossref PubMed Scopus (187) Google Scholar). This is particularly true for a group of 59 "early zygotic" genes that are transcribed well before the major transcriptional burst at the MBT. What of the trans-acting factors that regulate the changes in transcript populations during the MZT? Two-thirds of the unstable maternal transcripts—well over 1,000 distinct mRNA species genome-wide—are targeted for elimination by SMAUG, an evolutionarily conserved, RNA-binding posttranscriptional regulator (Tadros et al., 2007Tadros W. Goldman A.L. Babak T. Menzies F. Vardy L. Orr-Weaver T. Hughes T.R. Westwood J.T. Smibert C.A. Lipshitz H.D. Dev. Cell. 2007; 12: 143-155Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar), most likely by recruitment of the CCR4/POP2/NOT deadenylase (Semotok et al., 2005Semotok J.L. Cooperstock R.L. Pinder B.D. Vari H.K. Lipshitz H.D. Smibert C.A. Curr. Biol. 2005; 15: 284-294Abstract Full Text Full Text PDF Scopus (178) Google Scholar). Zygotic transcription, on the other hand, is potentiated by the CAGGTAG heptamer, which binds a previously identified protein, bicoid stability factor (BSF). Interestingly, BSF was originally identified as a posttranscriptional regulator (Mancebo et al., 2001Mancebo R. Zhou X. Shillinglaw W. Henzel W. Macdonald P.M. Mol. Cell. Biol. 2001; 21: 3462-3471Crossref Scopus (60) Google Scholar). Transcriptional potentiation of the early zygotic genes may serve as a timer that links spatially graded morphogens, such as DORSAL or BICOID, to temporal control of their target genes. Both components of the MZT—elimination of maternal mRNAs and transcription of a set of zygotic mRNAs—are conserved in all animals studied to date, including mammals (Hamatani et al., 2004Hamatani T. Carter M.G. Sharov A.A. Ko M.S. Dev. Cell. 2004; 6: 117-131Abstract Full Text Full Text PDF PubMed Scopus (667) Google Scholar). Since two major regulators of the Drosophila MZT, SMAUG and BSF, are evolutionarily conserved in both amino acid sequence and molecular function, it is plausible that the molecular mechanisms underlying the MZT are conserved in all animals.