MicroRNAs in Development and Disease

Abstract

Micro ribonucleic acids (miRNAs) are small RNAs responsible for selective repression and degradation of mRNAs. Regulation by miRNAs during development facilitates the transition from one stage to the next and can control specialized characteristics of mature cells. When this regulation is disrupted, cancer can result through increases in proliferation and defects in differentiation.

Keywords: microRNA; Dicer; development; developmental transition

Figure 1.

miRNA biogenesis and activity. miRNA precursors are processed by Drosha and Dicer to form mature miRNAs. After loading into miRNA‐induced silencing complex (miRISC), the miRNA acts to guide the complex to target mRNAs. Double‐stranded RNA can also be processed by a Dicer complex to generate small interfering RNAs (siRNAs) that are complementary to their target and mediate mRNA cleavage and degradation (Kosik, ; He and Hannon, ).

Figure 2.

Stepwise development of a mature cell from a stem cell. Progression towards a mature cell involves a number of intermediate stages. The cells that make up the early embryo are capable of giving rise to all cells in the organism. These totipotent cells divide and differentiate into different lineages, such as muscle or neuron, which in turn further develop to form the functional cell types present in the adult organism. The unique cellular properties of these cells must then be maintained throughout its lifetime. miRNAs act at each level to ensure controlled expression of stage‐specific factors and to facilitate transitions from one stage to the next.

Figure 3.

miRNAs in signalling cascades. miRNAs in signalling cascades can affect activity of the pathway in a number of ways. (a) An initial signal (S) may reinforce its own activity by activating an miRNA that downregulates a repressor (R) of the pathway. An example of this positive feedback loop is Notch signalling in C. elegans vulval precursor cells, as shown in the lower panel of (a). (b) Signalling cascades must be strictly regulated. An miRNA may finely tune expression of downstream signalling molecules through inhibition of a repressor of miRNA expression. For instance, regulation by miR‐430 of squint and lefty, genes that are involved in TGFß signaling, dampens and balances the input to the pathway to regulate the extent of mesoderm and endoderm differentiation. (c) Expression of several miRNAs within a pathway can act as a bistable switch to mediate the decision between cell fates. In the case of C. elegans chemosensory neurons, die‐1 signalling induces lsy‐6 expression, which then represses cog‐1, allowing the ‘left’ cell fate (ASEL) to be established. Alternatively, expression of miR‐273 in neurons inhibits die‐1 signalling so that lim‐6 is repressed and the ‘right’ cell fate (ASER) occurs.

Figure 4.

The importance of miRNAs in normal development. miRNAs aid the transition from one developmental stage to the following by repressing transcripts important to the earlier stage. As shown in this model (top), mRNAs for stem cell‐specific factors (green) are rapidly degraded upon miRNA expression (red). This clearance creates a clean slate for expression of lineage‐specific factors (blue). As mediators of transitions, both miRNA expression level and timing must be carefully regulated. In this model of a differentiating cell, a cell progresses from state A to B to C. In a normal state, the B–C transition occurs as an miRNA is activated and represses B state‐specific transcripts to sharpen and accelerate progression to the mature C state (top). If the miRNA is not expressed, B transcripts will accumulate, resulting in a mixed B/C cell state (middle). This cell, with properties of both the progenitor and mature cell, will likely be defective in performing its role in the adult organism. In a blocked state, premature miRNA expression results in downregulation of transcripts important for establishing the B state, and the cell remains in the A state (bottom). By inhibiting differentiation, the stem cell state is maintained. This model supports a common theory in cancer biology in which proliferation of the tumour is supported by a core of cancer stem cells (Choi et al., ).

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Further Reading

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Staton, Alison A, and Giraldez, Antonio J(Jul 2008) MicroRNAs in Development and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020863]