MicroRNAs and developmental timing

Abstract

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.

Figure 1. MicroRNAs and developmental timing in C. elegans

MicroRNAs (shaded text boxes) of the lin-4 and let-7-Family control the temporal progression of cell fates in the lateral hypodermal “seam” cell lineages of developing C. elegans larvae. In each of stages L1-L4, seam cells undergo a single round of stem cell-like self-renewal divisions (wedge-shaped bars), with a single symmetric division (red bar) interposed in the L2 stage. At the L4 molt, seam cells exit the cell cycle and terminally differentiate (triple bars). MicroRNAs post-transcriptionally regulate key target mRNAs by direct interactions (blue lines) with to 3′ UTR sequences. Down regulation of the transcription factor LIN-14 by lin-4 microRNA is required for progression from the asymmetric L1 division pattern to symmetric division in the L2. Progression from the L2 to the L3 fate is caused by the down regulation of the transcription factor HBL-1 through the redundant activity of microRNAs of the let-7 family, which includes let-7, mir-48, mir-84, and mir-241 [15]. let-7-Family microRNA activity is modulated positively by the TRIM/NHL protein NHL-2 [24]. The L2 to L3 transition also involves down regulation of the RNA binding protein LIN-28 by lin-4 microRNA; LIN-28 acts upstream of the let-7-Family microRNAs [15]. The nuclear hormone receptor is the hub of a complex set of interactions that integrate microRNA and steroid hormone inputs to coordinate temporal cell fates with a decision to enter an optional diapause after the L2 stage [14]. Progression from a cycling status to terminally-differentiation at the L4 molt is conferred by a dramatic up-regulation of let-7 in the L4, resulting in down-regulation of the TRIM/NHL protein LIN-41, and consequent up regulation of the transcription factor LIN-29. HBL-1 represses let-7 transcription, ensuring that the up regulation of let-7 microRNA occurs only after completion of earlier steps. The cessation of molting after the L4 stage involves in part the down regulation, by let-7 family microRNAs, of the nuclear hormone receptor molting factors NHR-23 and NHR25 [17].

Figure 2. Evolutionary conservation of developmental timing roles for microRNAs

A. In nematodes, insects and mammals, let-7 family microRNAs control progression from earlier, or more proliferative states, to later, more differentiated states. These conserved activities in developmental progression can involve explicitly conserved targets (red), and non-conserved targets (blue). C. elegans let-7 family microRNAs act in several cell types to control early-to-late cell fate progression. Examples of targets that are conserved between C. elegans and mammals and insects include LIN-28, LET-60/Ras and LIN-41. Nonconserved targets of let-7 can nevertheless mediate roles for let-7 in promoting transitions from more primitive to more differentiated developmental states: examples include in Drosophila the down regulation of Abrupt in the control of a reorganization of the neuromusculature at metamorphosis [45],[46], and in humans the down regulation of the oncogene HMGA2 [67]. B. MicroRNAs of families other than let-7 can also control temporal developmental transitions, such as the case of miR-96, which is required for a program of differentiation in mammalian inner ear hair cells [53]. There could be multiple relevant targets of miR-96 in this context, since many mRNAs are deregulated in mir-96 mutant mice [51].

Figure 3. MicroRNAs and transitions between pluripotency and differentiation

A. An evolutionarily conserved reciprocal repression between let-7 microRNA and LIN-28 results in mutually exclusive expression of LIN-28 between ES cells and differentiated cells, respectively. ES cell microRNAs (ESmirs) promote pluripotency and self-renewal together with other factors, including LIN-28, which acts in part by preventing expression of let-7. B. MicroRNAs miR-302 and miR-367 are expressed in stem cells of various types, including ES cells. Under certain conditions, experimental expression of miR-302 and miR-367 can be sufficient to reprogram mouse or human fibroblasts to induced pluripotent stem (iPS) cells [66].