Polarity and cell division orientation in the cleavage embryo: from worm to human

Abstract

Cleavage is a period after fertilization, when a 1-cell embryo starts developing into a multicellular organism. Due to a series of mitotic divisions, the large volume of a fertilized egg is divided into numerous smaller, nucleated cells-blastomeres. Embryos of different phyla divide according to different patterns, but molecular mechanism of these early divisions remains surprisingly conserved. In the present paper, we describe how polarity cues, cytoskeleton and cell-to-cell communication interact with each other to regulate orientation of the early embryonic division planes in model animals such as Caenorhabditis elegans, Drosophila and mouse. We focus particularly on the Par pathway and the actin-driven cytoplasmic flows that accompany it. We also describe a unique interplay between Par proteins and the Hippo pathway in cleavage mammalian embryos. Moreover, we discuss the potential meaning of polarity, cytoplasmic dynamics and cell-to-cell communication as quality biomarkers of human embryos.

Keywords: C. elegans; Drosophila; Hippo signalling; cytoplasmic flow; embryo; human; mouse; par proteins; polarity; preimplantation development.

Figure 1

Polarity in C. elegans, Drosophila and mouse oocytes and embryos. Polarized distribution of PAR proteins and accompanying factors in C. elegans zygote and 8-cell stage embryo (A), Drosophila oocyte, neuroblast and epithelium (B), and mouse oocyte and 16-cell stage embryo (C). In (A) and (B): A, anterior pole; P, posterior pole. In (C): A, animal pole; V, vegetal pole.

Figure 2

Interplay between PAR proteins and microtubules. Mechanism of a polarized dynein/dynactin-driven force exerted on microtubules in C. elegans (A), Drosophila (B) and mouse (C). Details in the main text. Boxes encircled with a dashed-line symbolize proteins that were not directly confirmed in the PAR proteins–microtubule interactions in the cleavage mouse embryos.

Figure 3

Cleavage patterns of mouse embryos at 2- to 4-cell transition. Two-cell stage mouse blastomeres divide either meridionally (M) or equatorially (E) giving rise to four types of embryos: ME, EM, MM and EE. Depending on the cleavage plane, progeny of the blastomeres populate different regions of the blastocyst (for details, see the main text). Moreover, embryos, which underwent at least one meridional division (ME, EM and MM), develop to term significantly more efficiently than EE embryos (data from Piotrowska-Nitsche and Zernicka-Goetz, 2005). A, animal pole; V, vegetal pole.

Figure 4

Regulation of Hippo pathway in 16-cell stage mouse embryo. Regulation of Yap phosphorylation and nuclear translocation in outer and inner cells. In outer cells, due to a lack of interaction between E-cadherin (E-cad), Merlin, Amot and Lats kinases Yap remains unphosphorylated and can access the nucleus, where it facilitates Cdx2 transcription. In inner cells, interaction between E-cad, Merlin and Amot activates Lats, leading to Yap phosphorylation and its sequestration in the cytoplasm. Details in the main text.