Micromanaging pattern formation: miRNA regulation of signaling systems in vertebrate development

Abstract

Early embryogenesis requires the establishment of fields of progenitor cells with distinct molecular signatures. A balance of intrinsic and extrinsic cues determines the boundaries of embryonic territories and pushes progenitor cells toward different fates. This process involves multiple layers of regulation, including signaling systems, transcriptional networks, and post-transcriptional control. In recent years, microRNAs (miRNAs) have emerged as undisputed regulators of developmental processes. Here, we discuss how miRNAs regulate pattern formation during vertebrate embryogenesis. We survey how miRNAs modulate the activity of signaling pathways to optimize transcriptional responses in embryonic cells. We also examine how localized RNA interference can generate spatial complexity during early development. Unraveling the complex crosstalk between miRNAs, signaling systems and cell fate decisions will be crucial for our understanding of developmental outcomes and disease.

Keywords: embryogenesis; miRNAs; pattern formation; signaling systems.

Figure 1.. miRNAs modulate signaling system levels in the early embryo.

(A) Varying levels of activation of signal transduction pathways yield distinct transcriptional outputs, delineating cell fate decisions. Cells receiving high levels of a particular signal near the source will become part of tissue 1, whereas cells farther away from the signal source which receive lower, if any, activation of the pathway will become part of tissue 2. (B) Tissue-specific expression of miRNAs (in tissue 2) results in dampened signaling system activity in intermediate cells (blue), resulting in formation of three distinct progenitor domains as compared to Fig. 1A.

Figure 2.. miRNAs can promote or repress signaling pathways.

(A) With repression, miRNAs targeting activators of Signal A ensures that Signal A is repressed, thus suppressing the gene regulatory program in red from being active in specified tissue 2 (cells in gray). (B) With activation, miRNAs targeting inhibitors of Signal B allow the activation of Signal B. Activation of Signal B specifies the gene regulatory program in blue to be activated in tissue B (cells in blue). Each example represents individual circumstances in which repression or activation of a signaling pathway can result in differentiation of specific tissues.

Figure 3.. Examples of miRNA regulation of signaling systems during embryonic patterning events.

(A) In the early chick embryo, miRNAs 200a, 20a, and 217, work in a concerted effort to target the FGF ligand and receptor, leading to decrease pathway activation in neural crest cells, as compared to the neighboring cell population, the neural plate. (B) In Xenopus miR-34 targets multiple components of the Wnt Signaling pathway, including the Wnt ligand, LRP, and the nuclear effectors β-catenin, and LEF1. In zebrafish, the mammalian ortholog of miR-25 targets β-catenin. Attenuation of the Wnt signaling pathway by miR-34 and miR-25 is essential for normal anterior posterior patterning in the early embryo. (C) In Zebrafish, miR-430 targets both the Nodal ligand, and its antagonist, Lefty, to balance Nodal signaling activation, leading to proper delineation of the developing mesoderm and endoderm. In human embryonic stem cells (hESCs), miR-302 targets the antagonist Lefty, but not the Nodal ligand, highlighting species specific targeting events via miRNAs.