B RIEFINGS IN FUNC TIONAL GENOMICS . VOL 11. NO 2. 107^117
doi:10.1093/bfgp/els004
Focus on miRNAs evolution: a
perspective from amphioxus
Simona Candiani
Advance Access publication date 28 February 2012
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression and thus control diverse
biological processes. The high interest in miRNAs as an important mediator of post-transcriptional gene regulation
has led to the discovery of miRNAs in several organisms. The present article outlines and discusses the current
status of miRNAs information on the basal chordate amphioxus and the evolution of miRNAs in metazoans.
Keywords: microRNAs; evolution; amphioxus; Hox genes; expression; microRNAs targets
INTRODUCTION
MicroRNAs (miRNAs) were recently discovered
both in plants and animals as a class of endogenous,
small (18–25 nt), non-coding, single-stranded RNAs
acting as post-transcriptional regulators [1–3].
miRNAs negatively regulate protein-coding genes
by binding, with imperfect complementarity, to
their 30 untranslated regions (UTRs), thereby blocking translation or subjecting the transcript to cleavage [4]. The biogenesis of a miRNA involves
several steps and multiple proteins [2, 5, 6]
(Figure 1). miRNAs regulate genes involved in development, cell differentiation and cell maintenance,
and are also involved in several neurodevelopmental
and neurodegenerative diseases as well as in brain
cancer [7–9].
The sequences of most miRNAs are conserved
across large evolutionary distances [10–13], and
many have restricted expression in different tissues
or organs. To gain insight into the fundamental
functions of miRNAs in vertebrates, it is important
to identify the miRNA repertoire of organisms
whose lineages diverged from the vertebrate lineage
before the origin of the vertebrates themselves, such
as the cephalochordate amphioxus, an emergent
model organism in the evo-devo field. Amphioxus
is a small, translucent animal, fish-like in appearance
and proportions, found in shallow marine waters in
various regions of the world (Figure 2).
Cephalochordates belong, together with urochordates and vertebrates, to the phylum Chordata and
possess vertebrate-like characters such as notochord,
pharyngeal gill slits, dorsal hollow nerve cord and
segmentally arranged muscles.
THE EVOLUTION OF miRNA
FAMILIES
It has been postulated that miRNA families are continuously added to metazoan genomes through geological time with minimal substitutions and rare
secondary losses [12–14]. No miRNA families
seem to have been present in the last common ancestor of metazoans but there have been at least four
major events of miRNA acquisition: one at the base
of nephrozoans (protostomes and deuterostomes),
while the others are at the branches leading to vertebrates, eutherians [15] and primates [16]
(Figure 3A). For deuterostomes (Figure 3B), each
species is characterized by the acquisition of novel
miRNAs with very little loss [17]. Therefore, a
survey of the literature, reported in [10, 11, 15,
18], concludes that the general trend of expanding
the microRNA repertoire in most lineages appears to
correlate with increasing complexity of animal
morphology.
Corresponding author. Simona Candiani, Laboratorio di Neurobiologia dello Sviluppo, Dip. Te. Ris., Università di Genova, Viale
Benedetto XV, 5, 16132 Genova, Italia. Tel.: þ39-(010)3538051; Fax: þ39-(010)3538047; E-mail: [email protected]
Simona Candiani graduated in Biological Sciences cum laude at the University of Genoa, PhD in Neurochemistry and
Neurobiology, assistant professor at the University of Genoa. At present, she is particularly interested in the study of the structure
and evolution of the central nervous system in chordates and the post-transcriptional control involved in the neuronal patterning and
neuronal differentiation.
ß The Author 2012. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]
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Candiani
Figure 2: Amphioxus Branchiostoma floridae collected
from Tampa Bay, Florida, USA.
Figure 1: miRNA biogenesis pathway. miRNA biogenesis begins with expression of a primary 1000 nt
miRNA transcript, termed pri-miRNA that is transcribed from a miRNA gene by RNA polymerase II
and then processed inside the nucleus into a 70 nucleotide hairpin-structured precursor (pre-miRNA) by a
RNAse III, called Drosha, in collaboration with Pasha/
DGCR8. After that, the pre-miRNA is transported by
exportin 5 into the cytoplasm and processed into a
miRNA duplex (miRNA:miRNA*) by another RNAse
III, Dicer, in collaboration with TRBP/PACT. Only one
strand of the miRNA:miRNA* duplex is assembled
with argonaute within the RNA-induced silencing complex (RISC), acting on its target gene by translational
repression or mRNA cleavage.
In recent years, researchers have tried to reconstruct the phylogeny of miRNAs in chordates. In
amphioxus, the first computational study [19] reported 28 miRNAs in the Branchiostoma floridae
(Figure 4). However, different approaches have led
to varying success in miRNA discovery in both
amphioxus and urochordates (tunicates). This can
lead to different phylogenetic hypotheses. The first
miRNA studies on urochordates and amphioxus suggested that amphioxus has conserved more miRNA
families with vertebrates than with protostomes or
other deuterostomes [20, 21] (Figure 4). More recently, Hendrix et al. [22], using a different computational program (Figure 4), identified 5-fold more
miRNAs in the tunicate Ciona intestinalis compared
with previous studies (70 miRNAs versus 331)
(Figure 4) and postulated that miRNA phylogeny is
consistent with the Olfactores hypothesis which
placed urochordata rather than cephalochordata as
the closest living relatives of vertebrates [23]. At the
same time, Campo-Paysaa etal. [17] reconstructed the
miRNA complement in five deuterostome lineages.
If both data sets are taken into account, C. intestinalis
appears to be more like to vertebrates than amphioxus. First of all, the total number of miRNAs in C.
intestinalis is actually higher (331) than amphioxus
(152). Moreover, B. floridae and C. intestinalis have
34 conserved miRNAs families, but C.intestinalis possesses 11 miRNAs uniquely shared with vertebrates
(miR-15, miR-101, miR-126, miR-132, miR-141,
miR-155, miR-181, miR-196, miR-199, miR-367
and miR-672) while B. floridae has only 2 (miR-19
and miR-129) (Figure 5). Therefore, C. intestinalis
seems to possess more vertebrate-like miRNAs than
amphioxus and few deuterostome-specific miRNAs.
However, if one considers the miRNAs isolated from
Branchiostoma japonicum [20] (Figure 5), a further 13
Focus on miRNAs evolution
109
Figure 3: Evolutionary acquisition of miRNA. (A) miRNA family gains are depicted at each node. Data for the
Strongylocentrotus purpuratus, Saccoglossus kowalevskii, Branchiostoma floridae and Petromyzon marinus are shown inside
of white circles and derived from [17]. Adapted with modifications from [12]. The x-axis measures millions of years.
Arrows show major miRNAs acquisitions. (B) Total miRNAs and miRNA families in five deuterostome species are
shown, as well gains and losses of miRNA families in each lineages.
Figure 4: miRNAs identification in amphioxus and
urochordates by using different experimental
approaches.
vertebrate/mammal-specific miRNAs are present in
amphioxus but absent from C. intestinalis.
Interestingly, the work by Dai etal. [20] is distinctive,
due to use of samples from embryonic amphioxus to
construct the libraries of small RNAs, whereas the
other data come from adults [13, 17, 21]. Taken together, these results show C. intestinalis and amphioxus
to
have
a
similar
number
of
‘vertebrate-specific’ miRNAs. However, as is the
case for several protein-coding genes, where the
loss of genes had occurred independently in the C.
intestinalis lineage [24], five miRNA families
(miR-10a, miR-100, miR-190, miR-193 and
miR-210) were lost in C. intestinalis while only one
family was lost in amphioxus (miR-153) (Figure 5).
Finally, C. intestinalis has some peculiar miRNAs such
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Candiani
Figure 5: Phylogenetic conservation of miRNAs in cephalochordates/urochordates within deuterostome and
chordate lineages. miRNAs from amphioxus (B. floridae), echinoderms (S. purpuratus), hemichordates (S. kowalevskii)
are from [17], whereas that of urochordates (C. intestinalis) and vertebrate species (zebrafish, Danio rerio; frog,
Xenopus tropicalis; chicken, Gallus gallus; mouse, Mus musculus; human, Homo sapiens) are from [22] and from
mirBase v17.0, respectively. New miRNAs from amphioxus Branchiostoma japonicum are represented as gray stars
and derived from [20].
Focus on miRNAs evolution
111
Figure 6: Evolution of miRNAs clusters. Examples of miRNAs clusters retained in both protostomes and deuterostomes, only in deuterostomes or only in chordates.
as moRs, which arise from the regions immediately
flanking the locations of the mature miR and miR*
products, as well as several antisense miRNAs
[22–25], that have been only rarely seen in other
species [26]. All aforementioned elements indicate
that consistent with previous findings of high rates
of molecular evolution in urochordates, their
miRNAs are very divergent from those of other
chordates. Indeed, Oikopleura dioica, a member of the
urochordate class Appendicularia, has only 8 of
49 miRNA families that are homologous to those
of other deuterostomes (Figure 4) [27].
EVOLUTIONARY IMPLICATION OF
miRNA CLUSTERING AND THEIR
LINKAGE WITH Hox GENES
miRNA gene clustering (groups of miRNAs genes
linked in the genome) is a common phenomenon in
metazoan genomes [28]. Conserved clusters of
miRNAs between distant species have been
described first in Drosophila melanogaster and mammals
[29], and subsequently in other deuterostomes [17].
As shown in Figure 6, examples of chordate-specific
miRNA clusters are miR-200/141 and miR-216/
217, whereas those conserved in all deuterostome
species are: miR-182/miR-96/miR-183, let-7/
miR-100/miR-125 and miR-1/miR-133 (the last
two are also present in protostomes). Moreover,
C. intestinalis has lost the cluster miR-29a/miR29b
found in all other deuterostomes, as well as the cluster miR-252a/252b/2001 found in Strongylocentrotus
purpuratus, Saccoglossus kowalevskii and B. floridae.
The functional consequences of this genomic
arrangement are still poorly understood, but there
are several hypotheses. Among the discovered
miRNAs, some are organized in the genome in
close proximity, aligned in the same orientation
and transcribed as a polycistronic structure from a
unique promoter, allowing them to function cooperatively in the same regulatory network [30].
For instance, all three miRNAs present in the cluster
mir-182/miR-96/miR-183 have a similar developmental expression pattern in sensory cells in vertebrates and invertebrates, and are transcribed as a
single polycistronic transcript in vertebrates [31]. At
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Candiani
Figure 7: Hox-related miRNAs in Drosophila, amphioxus and human.
the same time, the cluster miR-1/miR-133, present
in both protostomes and deuterostomes, is
muscle-specific [32, 33]. Moreover, miR-1 and
miR-133 are transcribed together and are involved
in mammalian muscle proliferation and differentiation [34]. Similarly, in amphioxus, mir-1 and
miR-133 are both in a polycistron, and both are
expressed in developing muscular somites [17].
Interestingly, several miRNA clusters are repeated
in the amphioxus genome and may be a result of
local tandem duplication [17, 19]. Such a mechanism, might explain the expansion of some
microRNA clusters not only in invertebrates but
also in vertebrates, even if in the latter the massive
expansion of the miRNA complement is also related
to the two rounds of genome duplication [18].
Another interesting aspect that has already excited
many developmental biologists is the evolutionary
conservation of miRNA and Hox gene connections.
Among the identified miRNAs some are located at
conserved genomic positions inside the Hox clusters
(Figure 7). In particular, in mammals two miRNAs
are present: miR-10 and miR-196 [35, 36]. miR-10
is present as two paralogues: miR-10a and miR-10b
which are associated with the 50 HoxB4 and HoxD4
genomic region, whereas miR-196 is present between Hox-9 and Hox-10 genes in the HoxA,
HoxB and HoxC cluster and no homologous has
been detected in the HoxD cluster. The emerging
idea is that such miRNAs regulate the upstream Hox
genes located within the clusters (Figure 7). In particular, miR-196 is expressed more posteriorly than
the target HOX genes, which likely helps to define
the posterior expression-boundary of these targets
[35, 36].
In arthropods, miR-10 is also found between the
Hox-4 and Hox-5 homologues (Dfd and Scr) [37].
A similar organization has been described in hemichordate, sea urchin and amphioxus [17]. miR-10 is
lost in urochordates and nematodes, probably reflecting the Hox cluster disintegration observed in these
species [38, 39]. Interestingly, Drosophila miR-10
resembles its mammalian counterpart because it is
found at an orthologous locus within the Hox cluster
(Figure 7), and it has the potential to target Hox
mRNAs (Scr) [40]. At the same time, amphioxus
miR-10-1 is able to recognize target sites in the
30 UTR of AmphiHox5 (Figure 7) [19].
Nevertheless, contrary to vertebrates, D. melanogaster
and amphioxus, miR-10 can regulate downstream
Hox genes in the cluster (Figure 7).
miR-196, emerged in the lineage leading to urochordates and vertebrates, but it is not present in
connection with Hox genes in the urochordate
Focus on miRNAs evolution
113
Figure 8: Conserved metazoan miRNAs evolved in a strictly tissue-specific context. Expression data are from
[17, 42, 43]. The ovals around some miRNAs correspond to the miRNAs studied in amphioxus. It is controversial
whether the last common ancestor of bilaterians had a centralized nervous system or an ectodermal nerve net.
C. intestinalis. Therefore, miR-196 could well have
been present in the ancestral urochordate, but
become lost as the Hox cluster split up and Hox
genes were lost in urochordates. However,
miR-196 in mammals, miR-10-3 in amphioxus
and miR-iab-4a in Drosophila are all together present
at similar positions in the Hox cluster and could represent an example of convergent evolution of gene
regulation. Both miR-196 and miR-iab-4a target
nearby Hox transcripts. Therefore, it is likely that
amphioxus Hox genes are subject to miRNA regulation and further experimental studies will be necessary to clarify the functional role of miRNAs in the
primordial Hox gene cluster of chordates.
EXPRESSION OF ANIMAL
microRNAs AND THE EVOLUTION
OF TISSUE IDENTITY: A LESSON
FROM AMPHIOXUS
There is evidence that miRNAs are critical in cell,
tissue and organ differentiation [41]. Among the
miRNAs identified in several organisms, very few
are expressed at early developmental stages, whereas
many of them are expressed in specific cells or tissues
and are important to keep cells in a particular
differentiation state. More recently, it was also proposed that changes in spatio-temporal expression of
miRNAs during evolution could result in significant
differences in physiology and morphology between
different organisms. Cristodolou et al. [42] have studied miRNA expression in species at key phylogenetic positions in order to understand whether the
evolution of body plans in bilateria is dependent
on miRNAs. In these organisms, there are sets of
conserved miRNAs specific for certain tissues and
cell types. Thus, the tissue-specific role of miRNAs
in the ancestor of bilaterians was proposed by comparing the expression of the annelid Platynereis
dumerilii miRNAs with those of other animal
models previously studied (such as D. melanogaster,
Caenorhabditis elegans and several vertebrates). For
example, the ancestral bilaterian is characterized by
miRNAs specific for different parts of brain or different cell types (central nervous system and peripheral nervous system, neurosecretory cells and sensory
organs), as well as miRNAs specific to musculature,
gut etc (Figure 8). As shown in Figure 8, the ancestor
of Eumetazoa is characterized by a mouth expressing
miR-100, the most ancient miRNA found in metazoans. Figure 8 also indicates the basal repertoire
of miRNAs found in different organ or cell types
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Candiani
Figure 9: miRNAs and central nervous system regionalization. miR-9, miR-124 and miR-184 expression compared
between amphioxus and fish brain. Brain regions are: TFB (telencephalic forebrain), DFB (diencephalic forebrain),
MB (midbrain), HB (hindbrain), SC (spinal cord), MHB (mid-hindbrain region). Putative brain regions in Platynereis
dumerilii are from [47].
of the ancestor of protostomes–deuterostomes. Interestingly, the emergence of miRNAs expressed in
different cell types of the ancestral bilaterian brain
could be linked to the appearance of a centralized
nervous system in these organisms, compared with
the simple nerve net found in the eumetazoan ancestor. Such a scenario seems to be confirmed by two
recent studies on miRNAs expression in amphioxus
[17, 43]. As described previously, B. floridae has a
cluster of miR-1/miR-133 expressed in somites at
neurula and larval stages [17]. Also in fly, P. dumerilii
and vertebrates, both miRNAs are expressed in the
differentiating musculature [32, 33, 42], with roles in
muscle proliferation and differentiation in at least
some of these species [32–34]. Moreover, amphioxus
possesses some miRNAs expressed in different cell
types of central nervous system (CNS) and peripheral
nervous system (PNS) that have counterparts in the
vertebrates and the ancestral bilaterian [43] (Figure
8). For example, miR-124 is widely expressed in the
CNS of fly, P. dumerilii, amphioxus (B. lanceolatum and
B. floridae) and vertebrates, as well as miR-183 and
miR-7/miR-137, which are linked to sensory organ
and neurosecretory cell development.
However, during chordate evolution some of
these miRNAs maintain the ancestral bilaterian
function, but others likely evolve new functions
and new tissue-specificity (Figure 8). For instance,
miR-9 is expressed in some cells associated with sensory organs in fly, P. dumerilii and Capitella sp. [42, 44]
but becomes CNS specific in amphioxus and all vertebrates (Figure 8). However, miR-9 in mammals is
broadly expressed in neural progenitor cells and at
lower levels in mature neurons [45, 46], whereas
amphioxus miR-9 is found only at later larval
stages and is likely not involved in neurogenesis [43].
Another interesting observation is the extreme
regionalization in the expression of miRNAs inside
the amphioxus CNS (Figure 9) [43]. For example, in
at least some invertebrates (such as P. dumerilii, D. melanogaster and S. purpuratus) and vertebrates, miR-124
and miR-184 are expressed in the entire brain; in
amphioxus miR-124 is absent in the almost all of the
anterior part of the CNS (the so called cerebral
vesicle homologized to the vertebrate diencephalic
forebrain and midbrain), while miR-184 is present in
the cerebral vesicle (Figure 9). Amphioxus shows
a domain of expression of miR-9 similar to that of
miR-124, although the cells expressing the two
miRNAs are not the same [43]. In zebrafish
embryos, miR-9 starts to be expressed in the telencephalon at 24 h and later spread throughout the
Focus on miRNAs evolution
CNS. Nevertheless, some areas of zebrafish brain
such as the midbrain–hindbrain boundary (MHB)
are devoid of miR-9 expression; through its absence
at the MHB, miR-9 regulates MHB correct positioning by targeting several components of the Fgf
signaling pathway and promotes progression of
neurogenesis in the regions adjacent to the MHB
[48]. The regionally restricted expression observed
in amphioxus CNS suggests that some miRNAs
could act not only in the differentiation of specific
cell types but also in the regionalization of the nervous system. More studies will be necessary to explore the functional roles of miRNAs in the
regionalization of the chordate CNS.
115
expressed in the nervous system, and only the targets
predicted by at least three algorithms have been considered as putative regulators of transcripts. By applying this procedure, the authors identified 17 putative
targets, 13 coexpressed with one or more of the
5 miRNAs and 6 not coexpressed, and thus they
hypothesized that amphioxus miRNAs likely regulate targets both by controlling translation and by
mRNA degradation. Nevertheless, additional functional studies are required to assess the quality of
predictions obtained with different approaches and
in different model organisms.
CONCLUSIONS
PREDICTION OF AMPHIOXUS
miRNA TARGETS
Several articles report computational methods for
miRNA target prediction in plants and animals.
Animal miRNAs exhibit generally imperfect
base-pairing, while plant miRNAs display almost
perfect complementarity [4]. This makes miRNA
target identification in animals more complex compared to that in plants. Furthermore, to understand
the role of miRNAs in animals, some authors have
proposed the comparison of the expression of
miRNAs and their putative target mRNAs
[49, 50].
At present, very few data are available for targets
of miRNAs in amphioxus, probably because the
transcripts in the genome of B. floridae have not
been fully annotated and many of them did not
contain the 30 -UTR regions where the target sites
are preferentially located. Computational prediction
of amphioxus miRNA target genes has been limited
to 49 protein-coding genes [19], with which 19
miRNAs are closely associated either in introns or
exons or in nearby non-coding regions. This analysis revealed that there is more than one predicted
target site for a given miRNA, a situation not uncommon and reflecting cooperative regulation of
transcription [51]. Moreover, no intronic miRNAs
have target sites within their host genes, while
intergenic miRNAs possess targets sites with neighboring genes such as the miR-10 target site in
AmphiHox-5.
Subsequently, four different prediction programs
(miRanda, RNAhybrid, FindTar and PITA) have
been used to predict the targets of 6 miRNAs expressed in the nervous system of amphioxus [43].
This study was performed on 68 coding genes
Although progress in our understanding of miRNA
biogenesis and post-transcriptional regulation has
been made, the role of specific miRNA in biological
functions is just now becoming established. This
review addresses our knowledge on phylogenetic
history of miRNAs in metazoans and chordates.
Accumulating data on miRNAs of amphioxus represents one more step in the understanding of
miRNA evolution along metazoans. However in
the near future more and more studies will be necessary in order to clarify the functional roles of
miRNAs. Further studies should be focused in particular on the expression of miRNAs and miRNA
target identification. Thus, the study of miRNA in
amphioxus may provide new insight into understanding the basic function of miRNAs in
vertebrates.
Key Points
Evolution of miRNA families: a comparison of the miRNA repertoires among metazoans and chordates. Phylogenetic conservation of urochordate and amphioxus miRNAs within the
deuterostome lineage.
Genomic organization of microRNAs in metazoans.
Evolutionary processes and functional role at the base of
miRNA clustering. Evolution of miRNAs located within Hox
gene clusters.
Expression of animal miRNAs and evolution of tissue identity.
Conservation of miRNA expression across species. Amphioxus
miR-124, miR-184 and miR-9 show regionalized expression domains in central nervous system. Prediction of amphioxus
miRNAs targets.
Acknowledgements
The author is indebted to the anonymous referees for their valuable comments and suggestions.
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Candiani
FUNDING
This work was supported by grant PRIN 20088jEHW3-001
from the Ministero dell’Istruzione, dell’Universitá e della
Ricerca (Italy).
21.
22.
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