The Maternal-to-Zygotic Transition During Vertebrate Development: A Model for Reprogramming

Abstract

Cellular transitions occur at all stages of organismal life from conception to adult regeneration. Changing cellular state involves three main features: activating gene expression necessary to install the new cellular state, modifying the chromatin status to stabilize the new gene expression program, and removing existing gene products to clear out the previous cellular program. The maternal-to-zygotic transition (MZT) is one of the most profound changes in the life of an organism. It involves gene expression remodeling at all levels, including the active clearance of the maternal oocyte program to adopt the embryonic totipotency. In this chapter, we provide an overview of molecular mechanisms driving maternal mRNA clearance during the MZT, describe the developmental consequences of losing components of this gene regulation, and illustrate how remodeling of gene expression during the MZT is common to other cellular transitions with parallels to cellular reprogramming.

Keywords: Cellular transitions; Maternal-to-zygotic transition; Pluripotency; Reprogramming; mRNA decay.

Figure 1. Features of cellular reprogramming

(a–c) Types of cellular reprogramming to pluripotency (a) In vivo fusion of oocyte and spermatazoon initiates the MZT during which the zygote is reprogrammed to a transiently totipotent embryo. (b) Nucleus from a differentiated cell is reprogrammed to a totipotent embryo when transplanted into enucleate fertilized oocyte (Gurdon, 1962). (c) In vitro, forced expression of four transcription factors OCT3/4, SOX2, KLF4, and c-MYC (Takahashi et al., 2006) or OCT3/4, SOX2, Nanog, and Lin28 (Yu et al., 2007) in differentiated cells induces a fraction of cells to reprogram to a pluripotent-like state called induced pluripotent stem cell (iPSC). (d) Model of cellular reprogramming: reprogramming between two cellular states involves (1) activation of the new program through gene transcription, (2) stabilization of that program through chromatin remodeling, and (3) removal of the previous state by post-transcriptional mechanisms.

Figure 2. Maternal and zygotic mechanisms of maternal mRNA clearance

(a) Maternal mRNAs under the regulation of the ‘maternal mode’ mechanisms (red) will be destabilized independently of zygotic transcription, while mRNAs under the ‘zygotic mode’ mechanisms (blue) will be stable in the absence of zygotic transcription. (b) Examples of characterized pathways of maternal and zygotic mode mechanisms across species. Maternal mode factors (red), zygotic mode factors (blue), and maternal factors activated after zygotic transcription (red with blue outline).

Figure 3. Combinatorial code in maternal mRNA clearance

(a) Cooperative mechanisms require both factors to destabilize mRNA, such that depletion of either one results in stabilization of the target mRNAs. Examples include EDEN-BP together with ARE-BP and miR-430 together with as-of-yet unidentified factor(s) (Ferg et al., 2007; Ueno & Sagata, 2002). (b) Redundant mechanisms require either factor, such that depletion of one of the factors does not affect the stability of target mRNAs. Examples include PCBP in C. elegans (Stoeckius et al., 2014) and Pumilio (Gerber et al., 2006) and BRAT (Laver et al., 2015) in Drosophila. Depleting both factors is required to block mRNA destabilization. (c) Model of combinatorial code for maternal mRNA clearance. Individual transcripts harbor multiple regulatory elements that affect mRNA stability. The combination of all signals acting on the mRNA determines mRNA fate.

Figure 4. The MZT is analogous to in vitro pluripotency reprogramming

(a) In zebrafish, the pluripotency factors Nanog, SoxB1, and Oct4 activate zygotic gene transcription, including miR-430, which clears maternal mRNAs (Giraldez et al, 2006; M. T. Lee et al., 2013). Together, the activation of the zygotic genome and the clearance of maternal mRNAs facilitate oocyte reprogramming to the zygotic state. (b) Forced expression of pluripotency factors reprograms somatic cells to induced pluripotent cells (Takahashi & Yamanaka, 2006; Yu et al., 2007) and miR-302 (orthologous to miR-430) is sufficient for reprogramming (Anokye-Danso et al., 2011; Miyoshi et al., 2011). (c) miR-430/302/294 family microRNAs are highly conserved, share seed sequence, and are expressed in stem cells and in early embryos (Houbaviy et al, 2003; Suh at al., 2004).