MicroRNAs and developmental timing

MicroRNAs regulate temporal transitions in gene expression associated with cell fate progression and differentiation throughout animal development. Genetic analysis of developmental timing in the nematode Caenorhabditis elegans identified two evolutionarily conserved microRNAs, lin-4/mir-125 and let-7, that regulate cell fate progression and differentiation in C. elegans cell lineages. MicroRNAs perform analogous developmental timing functions in other animals, including mammals. By regulating cell fate choices and transitions between pluripotency and differentiation, microRNAs help to orchestrate developmental events throughout the developing animal, and to play tissue homeostasis roles important for disease, including cancer.

Introduction

The roles for microRNA pathways in developmental timing were revealed by genetic analysis of worm mutants with particular kinds of defective larval cell lineages, in which events that are ordinarily restricted to specific stages of larval development occur at abnormal stages [1]. Cloning of the genes identified by these so-called heterochronic mutants of Caenorhabditis elegans led to the identification of the microRNA gene products of lin-4 [2^•] and let-7 [3^•]. lin-4 and let-7 regulate the timing of a wide variety of distinct developmental events in diverse cell lineages by progressively down regulating particular downstream targets (Figure 1), including the transcription factors LIN-14, HBL-1, and the TRIM protein LIN-41 [4]. MicroRNAs act post-transcriptionally on messenger RNA (mRNA) targets to which they base pair and repress production of the target protein. As post-transcriptional regulators with the ability to affect subtle changes in gene activity, microRNAs may be particularly suited for the regulation of the timing of events in diverse cell types and hence for coordinating the robust execution of temporal patterns of events throughout a developing organism.

While lin-4 and let-7 each exerts its effects on cell fate progression in worm larvae by down regulating a major target (LIN-14 and LIN-41, respectively), a different sort of developmental progression is managed by miR430 in the fish embryo. miR430 expression rises rapidly to very high levels at about four hours of embryonic development, and miR430 targets hundreds of maternal mRNAs for deadenylation and destruction. Thus, in this case a microRNA triggers a major developmental transition by coordinating the elimination of mRNAs whose function is complete [5].

Interestingly, the involvement of microRNAs in developmental timing is reprised in plants in a fashion quite analogous to C. elegans (reviewed in [6]). Heterochronic mutants of corn exhibit global developmental timing defects reminiscent of those in worms [7, 8]. One of these corn mutants, Corngrass1 was found to result from over expression of the microRNA miR156 [9]. The miR156 microRNA, along with other microRNAs, also controls developmental transitions in Arabidopsis [10, 11]. Plant microRNAs are not related to animal microRNAs, and so these parallel roles for microRNA pathways in plant and animals represent independent evolutionary adaptations of microRNAs to developmental timing roles.

Here I will review recent advances in understanding the microRNA pathways controlling developmental timing in C. elegans, and how those studies are illuminating principles of animal microRNA function in general. Emphasis will be placed on relating the functions of worm lin-4 and let-7 microRNAs to the functions of their orthologous microRNAs in mammals (mir-125 and let-7, respectively). I will also discuss findings showing that in vertebrates, other microRNAs (unrelated to lin-4/mir-125 or let-7) function analogously to the C. elegans heterochronic microRNAs to control the temporal progression of cell fates within cell lineages, and transitions between pluripotency and differentiation.