Principles and roles of mRNA localization in animal development

Abstract

Intracellular targeting of mRNAs has long been recognized as a means to produce proteins locally, but has only recently emerged as a prevalent mechanism used by a wide variety of polarized cell types. Localization of mRNA molecules within the cytoplasm provides a basis for cell polarization, thus underlying developmental processes such as asymmetric cell division, cell migration, neuronal maturation and embryonic patterning. In this review, we describe and discuss recent advances in our understanding of both the regulation and functions of RNA localization during animal development.

Fig. 1.

Examples of asymmetrically localized mRNAs. (A) Injected fluorescent RNA transcribed from the Vg1 vegetal localization element is localized to the vegetal cortex (bottom) of a stage III Xenopus oocyte. Image from J. Gagnon and K.M. (B) bicoid (green) and oskar (magenta) mRNAs accumulate, respectively, at the anterior and posterior poles of a Drosophila oocyte. Reproduced with permission from Bullock (Bullock, 2007). (C) IoEve mRNA accumulates at the centrosomes of a 4-cell-stage Ilyanassa embryo. RNA is shown in red, microtubules in green, DNA in blue. Reproduced with permission from Lambert and Nagy (Lambert and Nagy, 2002). (D) Apical accumulation of unpaired (upd) mRNA is shown in the Drosophila follicular epithelium. RNA is shown in red, microtubules in green, DNA in blue. Reproduced with permission from Van de Bor et al. (Van de Bor et al., 2011). (E) MS2-tagged pkp4 3′UTR reporter mRNAs are localized to pseudopodial protrusions of a cultured mammalian fibroblast. RNA is shown in green, cell morphology in red. Reproduced with permission from Mili et al. (Mili et al., 2008). (F) Camk2a (encoding CaMKIIα; red) and MAP2 (Mtap2; green) mRNAs are localized in dendrites of cultured mammalian hippocampal neurons. Boxed area is shown at higher magnification on the right. Reproduced with permission from Mikl et al. (Mikl et al., 2011).

Fig. 2.

Three distinct mechanisms underlying mRNA localization. (A-C) Three distinct mechanisms account for the asymmetric distribution of mRNAs within cells: localized protection from degradation (A), diffusion-coupled local entrapment (B) and directed transport along a polarized cytoskeleton (C). (A) Non-localized mRNAs are targeted by the degradation machinery, whereas localized mRNAs are protected by as yet unknown mechanisms. (B) mRNAs freely diffuse in the cytoplasm and are locally entrapped, at the cell cortex for example. (C) mRNAs destined for directional transport are recognized by specific trans-acting factors in the nucleus, where RNPs undergo different maturation steps. Upon export to the cytoplasm, RNP complexes are remodelled, and cytoplasmic factors ensuring coupling with molecular motors and transport along a polarized cytoskeleton are recruited. Once at the final destination, mRNAs are anchored and their translation is activated.

Fig. 3.

Localized maternal mRNAs in eggs and oocytes. (A) A stage 9 Drosophila oocyte is depicted, with accessory nurse cells shown on the left. bicoid mRNA (bcd, blue) is localized to the anterior margin of the oocyte and oskar mRNA (osk, purple) is localized to the posterior pole. gurken mRNA (grk, orange) is localized to the anterodorsal corner of the oocyte, adjacent to the oocyte nucleus. The anteroposterior and dorsoventral axes are indicated on the left. (B) A Xenopus stage IV oocyte is depicted, with Xdazl mRNA (blue) indicated at the vegetal pole and Vg1 (red), VegT (yellow) and Xvelo1 (purple) mRNAs shown at the vegetal cortex. (C) A zebrafish stage III oocyte is shown, with pou2 (green), bucky ball (buc, purple) and Vg1 (red) mRNAs localized to the animal hemisphere. Shown in the vegetal hemisphere are dazl (blue) and other vegetally localized mRNAs (orange). (D) A Clytia egg is depicted, with Wnt3 (red) and Frizzled1 (Fz1, green) mRNAs localized to the animal hemisphere, and Frizzled3 mRNA (Fz3, purple) localized to the vegetal hemisphere. (E) A fertilized Ascidian egg is depicted, with macho1 (purple) and PEM1 (blue) mRNAs localized to the vegetal cortex. (B-E) The animal-vegetal axis is indicated on the left.

Fig. 4.

Asymmetrically segregating mRNAs in dividing cells. (A) In Ilyanassa embryos, specific mRNAs (blue) localize to one of the two centrosomes of metaphasic cells at the 4-cell stage (left). Upon division, these mRNAs are differentially inherited by daughter cells (right). (B) Not mRNA (yellow) is delivered to one side of a Halocynthia embryo mesendoderm cell by nuclear migration. Not mRNA is inherited by the mesoderm daughter cell, but not the endoderm daughter cell. Adapted from Takatori et al. (Takatori et al., 2010). (C) Drosophila embryo neuroblasts (Nb) divide asymmetrically to regenerate a Nb and produce a smaller cell, the ganglion mother cell (GMC). Whereas inscuteable (insc) mRNA (orange) and Insc protein (red) localize at the apical side of interphasic Nb, prospero (pros) mRNA (yellow) and Pros protein (green) localize basally at anaphase, thus ensuring a differential inheritance of the two components. A, anterior; Ani, animal; P, posterior; Veg, vegetal.

Fig. 5.

Apicobasal mRNA targeting in epithelial cells. (A) In Drosophila follicular cells and embryonic epithelia, apical targeting of stardust (sdt, orange) mRNA is necessary to localize Crumbs (Crb, blue) and Sdt (red) proteins in young epithelial cells. At later stages, sdt mRNA is no longer apically distributed. (B) mRNA encoding zonal occludens-1 (ZO-1, purple) is targeted apically in mammalian mammary epithelial cells, which is necessary for the localization of its protein product (blue) to apical tight junctions. (C) wingless mRNA (wg, orange) accumulates at the apical pole of Drosophila embryonic epithelial cells, thereby promoting the secretion of Wg protein (red stars). hairy mRNA (light blue) is also localized at the apical side of epithelial cells, which would favour nuclear uptake of Hairy protein (dark blue stars). (D) dgrasp mRNA (orange) accumulates together with its product dGrasp (red) at the basal side of Drosophila follicular cells, in the zone of contact (ZOC) where it controls the basal targeting of integrin αPS1 mRNA (light green) and protein (dark green). The left panel represents a lateral view of the follicular epithelium, and the right panel a basal view. Adapted from Schotman et al. (Schotman et al., 2008).

Fig. 6.

Targeted mRNAs in migrating cells. (A) β-actin mRNA (light blue) or mRNAs encoding subunits of the Arp2/3 complex (light green) are targeted to the leading edge of migrating fibroblasts. Local synthesis of their corresponding proteins (dark blue and dark green stars, respectively) contributes to directional migration. (B) β-actin mRNA (light blue) is transported to the side of the axonal growth cone exposed to an attractive guidance cue (red). Locally translated β-actin protein (dark blue stars) accumulates at the same location, promoting the nucleation of actin filaments (purple) and triggering growth cone turning.

Fig. 7.

Local translation of dendritic mRNAs in response to synaptic activity. Translation of dendritically targeted mRNAs is activated in response to synaptic activity and is essential for modulation of synaptic activity and dendritic spine morphogenesis. Strikingly, translation can be regulated at the synapse level, and thus represents an efficient way to individually tag activated synapses. Upper left box: representation of the somatodendritic compartment of a mammalian neuron. Lower panel: schematic of the proximal part of a dendrite that roughly corresponds to the region boxed in the upper panel (red rectangle). Proteins synthesized locally in dendritic spines are represented in green.