Most animals develop from juveniles, which cannot reproduce, to sexually mature adults. The most obvious signs of this transition are changes in body shape and size. However, changes also take place in the brain that enable the animals to adapt their behavior to the demands of adulthood. For example, fully fed adult male roundworms will leave a food source to search for mates, whereas juvenile males will continue feeding.

The transition to sexual maturity needs to be carefully timed. Too early, and the animal risks compromising key stages of development. Too late, and the animal may be less competitive in the quest for reproductive success. Cues in the environment, such as the presence of food and mates, interact with timing mechanisms in the brain to trigger sexual maturity. But how these mechanisms work – in particular where and how an animal keeps track of its developmental stage – is not well understood.

In the roundworm species Caenorhabditis elegans, waves of gene activity, known collectively as the heterochronic pathway, determine patterns of cell growth as animals mature. Through further studies of these worms, Lawson et al. now show that these waves also control the time at which neural circuits mature. In addition, the waves of activity occur inside the nervous system itself, rather than in a tissue that sends signals to the nervous system. Moreover, they occur independently inside many different neurons. Each neuron thus has its own molecular clock for keeping track of development.

Several of the genes critical for developmental timekeeping in worms are also found in mammals, including two genes that help to control when puberty starts in humans. If one of these genes – called MKRN3 – does not work correctly, it can lead to a condition that causes individuals to go through puberty several years earlier than normal. Studying the mechanisms identified in roundworms may help us to better understand this disorder. More generally, future work that builds on the results presented by Lawson et al. will help to reveal how environmental cues and gene activity interact to control when we become adults.

The timing of sexual maturation is subject to complex regulation that reflects competing demands on biological systems (Bogin et al., 2011; Gluckman and Hanson, 2006; Parent et al., 2003). Over evolutionary time, the pressure on a species to reproduce rapidly is countered by the need to allow sufficient time for robust juvenile development. Optimum balance of these pressures is encoded by internal, genetic mechanisms that guide the timing of the juvenile-to-adult transition (Zhu et al., 2018). At the level of an individual, internal and external stimuli—for example the presence of mates and food, as well as health and nutritional status—interact with these timers to determine the onset of sexual maturation (Abreu and Kaiser, 2016; Avendaño et al., 2017; Livadas and Chrousos, 2016; Plant, 2015).

In general, the nature of these genetic timers and their interaction with other signals is not well understood. Furthermore, while the hallmark of the juvenile-to-adult transition is the functional maturation of the germline and genitalia, reproductive maturation is typically accompanied by a much broader suite of changes in morphology, physiology, and behavior. These behavioral changes entail not only the activation of copulatory programs themselves, but also include modifications to decision-making circuits, allowing animals to incorporate reproductive drives when prioritizing behavioral programs. Whether genetic timers function at a single hub to coordinate behavioral transitions, or whether instead they may have distributed functions across different cell types, is unclear.

The timing of sexual maturation has been extensively studied in mammals, where it is coordinated by the temporally controlled production of gonadal steroids at puberty (Abreu and Kaiser, 2016; Avendaño et al., 2017; Livadas and Chrousos, 2016; Plant, 2015). This process is activated by the hypothalamic-pituitary-gonadal (HPG) axis, in which the pulsatile release of gonadotropin-releasing hormone (GnRH) by neurons in the hypothalamus activates gonadotropin production in the pituitary gland. This, in turn, triggers gonadal maturation and subsequent steroid hormone production. Upstream of HPG axis activation, a complex set of regulatory inputs converges on the release of the neuropeptide kisspeptin in the arcuate nucleus of the hypothalamus to stimulate GnRH production. Multiple studies suggest that kisspeptin release is influenced by environmental signals as well as internal timing cues (Harter et al., 2018). Recent studies in mice and humans have identified a number of genes important for this process, including the miRNA regulators LIN28A/B, their target LET7, and the Makorin MKRN3, whose loss causes Central Precocious Puberty in humans (Abreu et al., 2013; Corre et al., 2016; Gajdos et al., 2010; Ong et al., 2009; Park et al., 2012; Yi et al., 2018; Zhu et al., 2010; Zhu et al., 2018). However, where and how these genes act to regulate the onset of reproductive maturation remains unclear. Moreover, some aspects of this model are likely to be specific to mammals, highlighting the importance of studying these questions in diverse animals.

In the nematode C. elegans, juveniles pass through four larval stages before becoming sexually mature adults, offering an ideal opportunity to understand the mechanisms that regulate the juvenile-to-adult transition. Most studies addressing this question have focused on stage-specific events during larval development, particularly in the hypodermal seam cells, epidermal-like cells that lie along the sides of the body. In seam cells, stage-specific patterns of proliferation and differentiation are controlled by a complex mechanism known as the ‘heterochronic pathway’ (Rougvie and Moss, 2013). In this mechanism, temporally controlled waves of miRNA expression (including the first two miRNAs discovered in any system, lin-4 and let-7) act on a variety of targets to specify stage-specific events and regulate the transition from one stage to the next. The conserved miRNA regulator lin-28 is also a key component of this mechanism. The heterochronic pathway also controls some events that occur during the larval-to-adult transition, including the cessation of molting, the fusion of the seam cells, and male-specific tail tip morphogenesis (TTM), a remodeling of four postmitotic posterior hypodermal cells (Del Rio-Albrechtsen et al., 2006; Rougvie and Moss, 2013). In some heterochronic mutants (‘precocious’ mutants), particular stage-specific events are skipped or occur too early; in others (‘retarded’ or ‘delayed’ mutants), events are delayed or absent.

Recent studies of TTM have identified two additional heterochronic genes, lep-2/Makorin and the lncRNA lep-5, that influence developmental timing by regulating LIN-28 stability (Herrera et al., 2016; Kiontke et al., 2019). Mutations in these genes cause a delayed phenotype, the retention of a larval-like, pointed (‘Lep’) tail tip in males. These mutants also have developmental defects in the body hypodermis, but they lack the seam cell lineage disruptions of other heterochronic mutants. Interestingly, lep-2 mutant males have defects in mating behavior, suggesting a role for lep-2 in the sexual maturation of the nervous system (Herrera et al., 2016).

While the maturation of the hypodermis has been well studied, the mechanisms that control the timing of adult-specific sexual behavior in C. elegans are poorly understood. In both sexes, males and hermaphrodites (somatic females that produce both eggs and sperm), sexual behavior requires larval neurogenesis that produces sex-specific circuits for copulation and egg-laying behavior (Emmons, 2018; García and Portman, 2016). The development of these circuits is independent of the gonad, relying instead on intrinsic lineage programs in which chromosomal sex acts via the sex-determination hierarchy to regulate neurogenesis and cell fate specification (Barr et al., 2018). Furthermore, multiple aspects of adult male behavior also require changes in synaptic connectivity and the functional modulation of pre-existing, post-mitotic neurons and circuits at the juvenile-to-adult transition (Portman, 2017). For example, the AWA olfactory neurons express the food-associated chemoreceptor odr-10 in larvae of both sexes, but in males, odr-10 expression is repressed at the larval-to-adult transition. This repression desensitizes males to food stimuli and promotes mate-searching behavior (Ryan et al., 2014). In other cases, adult-specific activation of gene expression in males, such as the expression of daf-7 in the ASJ neurons (Hilbert and Kim, 2017) facilitates adult behavior. The extent to which sex-shared, postmitotic neurons are functionally modulated at the juvenile-to-adult transition remains unclear, and the mechanisms that control the timing of this modulation are unknown.

The striking involvement in mammalian puberty of orthologs of three C. elegans heterochronic genes (lep-2, lin-28, and let-7), together with the emerging appreciation that C. elegans sexual differentiation involves functional transitions in post-mitotic neurons, led us to explore the role of the heterochronic pathway in the timing of these changes. We find that the lep-2/lep-5 branch of the heterochronic pathway plays a key role in timing the sexual differentiation of the C. elegans nervous system, demonstrating conservation of mechanism across species and raising the possibility that an unidentified lep-5-like lncRNA may play a key role in mammalian sexual maturation. Moreover, we find that this pathway acts cell-autonomously in multiple neurons, suggesting that genetic timing information is widely distributed across the nervous system. Multiple targets of lin-41, including mab-3 and lin-29a, integrate the heterochronic and sex-determination pathways to regulate downstream effector genes and the activation of multiple adult behaviors. Interestingly, although the mammalian Makorin MKRN3 functions in the opposite direction as its C. elegans ortholog lep-2, we find that MRKN3 expression in the C. elegans nervous system is sufficient to delay sexual maturation, indicating that the pathway in which it interacts is functionally conserved across species. These findings identify the heterochronic pathway as an ancient regulator of sexual differentiation of the nervous system, provide specific mechanistic hypotheses for the functions of these genes in the mammalian brain, and suggest an important role for a yet-unidentified mammalian lncRNA in the timing of puberty.

Although it has long been appreciated that animal behavior undergoes functional transitions commensurate with sexual maturation (Spear, 2000), the mechanisms that determine the timing of these changes are poorly understood. Indeed, in humans, adolescence is a period of heightened susceptibility to a variety of neuropsychiatric disorders (Jones, 2013; Walker et al., 2017), highlighting the importance of understanding the regulatory mechanisms that control these transitions. Here, we unite disparate findings from studies of mammalian puberty and C. elegans developmental biology to establish that a conserved developmental timer functions cell-autonomously to coordinate the sexual maturation of the C. elegans nervous system (Figure 6). Central to this mechanism is the temporal control provided by the lncRNA lep-5, which, together with the Makorin lep-2, promotes the timely decay of the conserved miRNA inhibitor LIN-28 (Kiontke et al., 2019). This decay permits the biosynthesis of mature let-7 miRNA and, through the pathway shown in Figure 6, promotes the juvenile-to-adult transition.

Figure 6

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The maturation events we have studied here entail not the incorporation of new neurons and circuits into the nervous system, but rather gene expression and functional changes in pre-existing, postmitotic neurons. As such, these events parallel similar changes in the mammalian hypothalamus, where both gene expression and physiological changes determine the timing of HPG axis maturation and the onset of puberty (Abreu and Kaiser, 2016; Avendaño et al., 2017; Livadas and Chrousos, 2016; Plant, 2015). Because MKRN3, LIN28A/B, and LET7 are expressed in the hypothalamus and elsewhere in the mammalian brain, our results indicate that the neuronal function of the heterochronic pathway is an ancient regulator of the juvenile-to-adult transition. In this view, the activational effects of gonadal steroids at puberty (McCarthy et al., 2012) are likely to be a recent evolutionary adaptation that reinforces sexual differentiation of the mammalian nervous system via an endocrine feedback loop. Moreover, it suggests that puberty-independent events outside the hypothalamus that contribute to behavioral maturation during mammalian adolescence, such as the transition from play to aggression in Siberian hamsters (Paul et al., 2018), could also be timed by the heterochronic pathway.

In addition to identifying neuronal functions for lep-2, lin-28, and let-7, we also show that the recently identified lncRNA lep-5 functions in this pathway. lep-5 was identified in forward genetic screens for male tail morphogenesis defects; in lep-5 mutants, LIN-28 protein persists longer than in wild-type, delaying the onset of expression of dmd-3, the master regulator of tail tip morphogenesis (Kiontke et al., 2019). Because lep-5 is expressed in a temporal wave whose rise corresponds to the time at which lin-28 expression decays, lep-5 is thought to provide an instructive temporal cue for the destabilization of LIN-28 and, in turn, allow production of the let-7 miRNA and the progression through late-larval development. Because lep-2 mutants have a phenotype essentially identical to that of lep-5, Kiontke et al., 2019 have proposed that lep-5 serves as an RNA scaffold that recruits both LEP-2 and LIN-28; such a model is supported by in vivo crosslinking experiments demonstrating that lep-5 binds to both LEP-2 and LIN-28. As a member of the Makorin family, LEP-2 may possess both RNA-binding and putative E3 ubiquitin ligase activities (Herrera et al., 2016), suggesting that a tripartite LEP-2–lep-5–LIN-28 complex could destabilize LIN-28 through ubiquitination by LEP-2 (Kiontke et al., 2019). Sequence homologs of lep-5 have not been found outside of nematodes; however, lncRNAs are known to evolve rapidly, usually making it impossible to identify orthologs based on primary sequence alone (Diederichs, 2014). It is tempting to speculate that structural and/or functional orthologs of lep-5 are present in mammals and could have an important role in the regulation of LIN28 and its control of puberty.

Intriguingly, mammalian MKRN3 has the opposite effect on developmental timing as its C. elegans ortholog lep-2. While lep-2 mutant adults exhibit juvenile characteristics in the male tail tip (Herrera et al., 2016) and nervous system (this work), null or hypomorphic mutations in human MKRN3 lead to Central Precocious Puberty (Abreu et al., 2013), in which children younger than eight (girls) or nine (boys) years of age develop secondary sexual characteristics. This may reflect a generally more complex role for a putative MKRN3–LIN28–LET7 regulatory module in mammalian puberty compared to C. elegans sexual maturation. For example, overexpression of Lin28a delays puberty in male and female mice (Corre et al., 2016; Zhu et al., 2010), consistent with the maturation-inhibiting function of C. elegans lin-28. However, Lin28b^–/– mice, as well as mice overexpressing let-7, also exhibit delayed sexual maturation, in contrast to the roles of lin-28 and let-7 in C. elegans; moreover, these effects were seen only in males (Corre et al., 2016). In mammals, these genes can be easily imagined to function at multiple steps in sexual development, such that apparently antagonistic activities could arise from roles for the mammalian heterochronic pathway in the production of both maturation-promoting and maturation-inhibiting signals. Clarification of these issues will require regionally and temporally controlled manipulations of mammalian gene activity. Here, we found that human MKRN3 was not able to rescue the defects of C. elegans lep-2 mutants. Remarkably, however, MKRN3 overexpression caused a slight delay in the sexual maturation of two neuron types, AIM and AWA, in the C. elegans nervous system. This strongly suggests that the biochemical functions of LEP-2 and MKRN3 are not equivalent, and, moreover, that the mechanism by which MKRN3 regulates pubertal timing is conserved in C. elegans. Several potential models are consistent with these observations (Figure 6). MKRN3 might inhibit LEP-2, perhaps through a dominant-negative mechanism in which MKRN3 binds to lep-5 but is unable to recognize C. elegans LIN-28. Alternatively, MKRN3 might somehow stabilize LIN-28, rather than promoting its degradation, or, less likely, MKRN3 could function in parallel with the lep-2—lin-28 module. Further, we cannot rule out the possibility that MKRN3 overexpression artifactually inhibits lep-2 function.

Ours are not the first studies to examine roles for the heterochronic pathway in the C. elegans nervous system. Early in larval development, the timing of synaptic remodeling of a class of GABAergic motorneurons is controlled by the heterochronic gene lin-14, which specifies multiple aspects of the L1 stage (Hallam and Jin, 1998). Later, a hermaphrodite-specific aspect of nervous system maturation, the outgrowth of the HSN axon, is controlled by lin-14 and lin-28 (Olsson-Carter and Slack, 2010). However, in neither case have the relevant targets of heterochronic function been identified. Interestingly, the heterochronic pathway, particularly let-7 and lin-41, also has a role in regulating damaged-induced regeneration of the AVM axon in adults, an ability that declines with age (Zou et al., 2013). Moreover, studies in Drosophila also support a role for the heterochronic pathway in the timing of major transitions in the nervous system (Faunes and Larraín, 2016). let-7 and related miRNAs control temporal specification of neuronal fate at the larval-to-pupal transition (Chawla et al., 2016; Marchetti and Tavosanis, 2017; Wu et al., 2012); they also regulate remodeling of neuromuscular anatomy and function at the pupal-to-adult transition (Caygill and Johnston, 2008; Sokol et al., 2008). Recently, Drosophila lin-28 has been found to be widely expressed in the nervous system in late third instar larvae, and loss of lin-28 function accelerates the larval-to-pupal transition (González-Itier et al., 2018). Together, these findings indicate an ancient role for this regulatory module in orchestrating developmental transitions in the nervous system.

Work carried out in parallel with the studies reported here (Pereira et al., 2019) found that the heterochronic pathway acts cell-autonomously to control several other aspects of male-specific sexual differentiation, including a neurotransmitter fate switch and changes in synaptic connectivity. Interestingly, Pereira et al. identified lin-29a, a male-specific isoform of lin-29, as a key mediator of many of these transitions, acting to integrate temporal and sexual signals. Here, our studies consider other aspects of male-specific functional maturation and focus on upstream components of the heterochronic pathway, particularly lep-2 and lep-5, best known for their roles in male tail development (Herrera et al., 2016; Kiontke et al., 2019). The strong nervous system phenotypes of these mutants indicate that this specialized branch of the heterochronic pathway is critical for the sexual maturation of the nervous system. Moreover, these studies strongly suggest that the function of MKRN3 in regulating human puberty is related to the LIN28–LET7 axis and predict the central involvement of a yet-unidentified lncRNA in this process.

Though all of the maturation events we have studied here are male-specific, the heterochronic pathway almost certainly has a role in hermaphrodite-specific and non-sex-specific maturation of the C. elegans nervous system as well. Indeed, as mentioned above, differentiation of the hermaphrodite-specific HSN neuron requires heterochronic function (Olsson-Carter and Slack, 2010); however, little is known about non-male-specific changes in neuronal function that accompany sexual maturation. Interestingly, two recent studies have demonstrated functional transitions in chemosensory coding and behavior that occur at the juvenile-to-adult transition in hermaphrodites (Fujiwara et al., 2016; Hale et al., 2016). In one of these cases (Fujiwara et al., 2016), signaling from the gonad plays an important role, raising the more general possibility that signals from the gonad could intersect with cell-autonomous timers to provide more flexible control of behavior.

Although the phenomena we have studied here derive their sex-specificity by the integration of temporal and sexual signaling at the level of mab-3 and lin-29a, other interactions between sex-determination and heterochronic timing are likely. By ChIP-seq studies, lin-28 has been identified as a direct target of tra-1 (Berkseth et al., 2013); both tra-1 and tra-2 are potential targets of the miRNA let-7 (targetscan.org); the abundance of TRA-1 protein has been shown to be developmentally regulated (Weinberg et al., 2018) (H.L. and D.S.P., in prep.); and some phenotypes of heterochronic mutants can be considered sexual transformations (Ambros and Horvitz, 1984). Interestingly, many aspects of the timing of mammalian puberty also appear to be sex-specific (Abreu and Kaiser, 2016; Cousminer et al., 2016). Together, these observations blur the distinctions between sexual differentiation mechanisms and developmental timing pathways, helping provide a mechanistic understanding of the observation that sexual dimorphism often arises through heterochrony (McNamara, 2012). Because the deep crosstalk between sexual and temporal information is unlikely to be limited to C. elegans, reproductive maturation disorders and sex-biased disorders of the nervous system in humans will both be informed by a deeper appreciation of these intersections.

Data is available in supporting files.

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Author details

1. Hannah Lawson

   Department of Biology, University of Rochester, Rochester, United States

   Contribution

   Conceptualization, Resources, Formal analysis, Investigation, Writing—original draft

   Competing interests

   No competing interests declared

2. Edward Vuong

   Department of Biomedical Genetics, University of Rochester, Rochester, United States

   Contribution

   Conceptualization, Investigation

   Competing interests

   No competing interests declared

3. Renee M Miller

   Department of Brain and Cognitive Sciences, University of Rochester, Rochester, United States

   Contribution

   Conceptualization, Formal analysis, Investigation

   Competing interests

   No competing interests declared

4. Karin Kiontke

   Center for Developmental Genetics, Department of Biology, New York University, New York, United States

   Contribution

   Conceptualization, Resources, Investigation

   Competing interests

   No competing interests declared

5. David HA Fitch

   Center for Developmental Genetics, Department of Biology, New York University, New York, United States

   Contribution

   Conceptualization, Resources, Funding acquisition

   Competing interests

   No competing interests declared

6. Douglas S Portman

   1. Department of Biology, University of Rochester, Rochester, United States
   2. Department of Biomedical Genetics, University of Rochester, Rochester, United States
   3. Department of Neuroscience, University of Rochester, Rochester, United States
   4. DelMonte Institute for Neuroscience, University of Rochester, Rochester, United States

   Contribution

   Conceptualization, Formal analysis, Supervision, Funding acquisition, Writing—review and editing

   For correspondence

   douglas.portman@rochester.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2686-8839

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