What does the term heterochronic mean? Heterochronic refers to the development of cells or tissues at an abnormal time relative to other unaffected events in an organism; the latter can thus serve as temporal landmarks. Mutations in heterochronic genes cause certain cells to adopt cell fates normally associated with earlier or later times in development. Heterochronic genes therefore regulate the timing and sequence of developmental events in specific cell lineages, and thereby coordinate events throughout a developing organism. Why study heterochronic genes in worms? The nematode Caenorhabditis elegans provides a particularly tractable model for studying heterochronic genes, owing to its relatively simple and invariant cell lineages. In the four larval stages of its post-embryonic development, C. elegans cells exhibit stage-specific patterns of developmental events, such as cell division and cell fate specification, with each stage separated by a molt. Importantly, neither larval growth nor progression through the molting cycle in the worm are affected by known heterochronic mutations, allowing developmental events to be monitored relative to these temporal landmarks. So, is this just a strange worm phenomenon? No. Heterochronic genes have been reported in many different organisms, including Drosophila (hunchback, Krüppel, pdm, castor) and several species of plants, including Arabidopsis (HASTY) and rice (mori1). What do heterochronic genes do in worms? One class of heterochronic mutations results in an early, or precocious, phenotype in which many of the normal cell fate decisions of a specific larval stage are skipped and much of the worm instead executes the developmental program of a later stage. Examples include mutations in lin-14, lin-28 and lin-41. Worms with such mutations express adult cell fates when the animal is still sexually immature (Figure 1). Conversely, a second class of mutations results in a delayed, or retarded, phenotype in which many normal cell fate decisions are reiterated in subsequent larval stages. Examples include mutations in lin-4 and lin-29. Worms with such mutations do not express certain adult cell fates, despite being sexually mature (Figure 1). Is there conservation in heterochronic gene pathways? An important regulator of the larval-to-adult transition in worms, let-7, is conserved across diverse phyla, having been identified in flies, sea urchins, humans and many other organisms. In addition, it has recently been demonstrated that the C. elegans heterochronic gene lin-57 is a worm homolog of the Drosophila gene hunchback (hence its new name hbl-1). In the developing central nervous system of flies, hunchback regulates the temporal patterning of cell fate specification for neuroblasts. But doesn't hunchback regulate spatial patterning in flies?Hunchback is indeed best known for its role in anterior–posterior patterning in the early fly embryo; it encodes a zinc-finger transcription factor that acts to establish spatial domains of gene expression. Although downstream effectors are unknown in worms, it is possible that hbl-1 is able to establish analogous temporal domains of gene expression. What's the deal with microRNAs and how are they involved in the heterochronic gene pathway? microRNAs are now appreciated as a new class of small non-coding RNAs. They are likely to act by regulating translation of target mRNAs through binding to sequences in the 3′ untranslated regions with partial anti-sense complementarity. When the product of the lin-4 heterochronic gene was found to be a small, non-coding RNA in 1993, it appeared that it might be a C. elegans-specific, molecular oddity. A second small non-coding RNA, let-7, was discovered in the heterochronic gene pathway in 2000, followed by the cloning of hundreds of small non-coding RNAs (microRNAs) in 2001 and beyond, and it is now appreciated that the heterochronic genes lin-4 and let-7 are the founding members of a larger microRNA gene family. Are microRNAs involved in other pathways? Although the first two microRNAs identified are in the heterochronic gene pathway, there is now evidence for roles of microRNAs in cell proliferation, cell death, fat metabolism and stress resistance in flies. Is there anything we don't know? The mechanism of action of many heterochronic genes remains to be determined. For example, lin-14 encodes a novel nuclear protein with no identified downstream effectors to date. In addition, emerging evidence of phylogenetic conservation of heterochronic genes leads to the prospect that mechanisms to control developmental timing will be elucidated in other systems. Where can I find out more?
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Open Access
Apr 18, 2019
Fumihiro Ito + 2
