14-3-3zeta/leonardo
The D14-3-3 gene (14-3-3zeta or Leonardo) expresses 1.0-, 1.9- and 2.9-kb mRNAs, all of which show differential expression patterns. While the 2.9-kb mRNA is expressed only in the head, the other two mRNAs are found both in the head and body. Compared to the 1.9- and 2.9-kb mRNAs, the 1.0-kb mRNA is more abundant in the ovary and is probably maternally inherited. The 1.9-kb mRNA is the most predominant species in the embryo; its level peaks between 6-15 h of embryogenesis. The D14-3-3 gene is predominantly expressed in the ventral nerve cord of the embryo, and in the neural tissues of the head (Swanson, 1992).
In addition to a strong 14-3-3zeta expression in the central nervous system, an enrichment of the transcript is seen in the region posterior to the progressing morphogenic furrow of the developing eye imaginal disc. 14-3-3zeta (Leonardo) is expressed in most, if not all cells of the eye disc. Strong antibody staining levels are found in the region posterior to the morphogenetic furrow where cells undergo neuronal induction and differentiation as photoreceptors. Within these cells, the distribution of protein appears to be concentrated apically, showing a subcellular pattern similar to the distribution of proteins that act upstream of Raf, such as Boss, Sevenless, EGF receptor, Drk, Sos and Dos (Kockel, 1997)
Antisense probes produce remarkably intense signal in mushroom body cells. Lower levels of hybridization are observed in cells of the subesophageal ganglion, optic lobes, antennal lobes, and the central brain. The gene is also expressed in cells of the thoracic ganglia, nurse cells, and maturing oocytes of female flies (Sokoulakis, 1996).
Antibody preferentially decorates the neuropil of the mushroom bodies. The antigen is detected in the dendritic projections (calyces), the cytoplasm of the parikarya, and the axonal projections that form the peduncle and lobes of the mushroom body neurons. In addition, the antibody decorates the ellipsoid body, a neuropil structure of the central complex and a group of cell bodies residing just anterior to the "heel" of the mushroom bodies. These cells appear to be the ring neurons that project to the ellipsoid body. The antibody also decorates neuropil and cell bodies in the antennal lobes, albeit with lower intensity. In sagittal sections, modest staining is observed in thoracic ganglia and throughout the cytoplasm of nurse cells and oocytes (Sokoulakis, 1996).
Immunological localization of the Leonardo protein shows that it is expressed at synaptic
connections and enriched in presynaptic boutons of the neuromuscular junction (NMJ). Null leonardo
mutants die as mature embryos. Electrophysiological assays of the mutant NMJ demonstrate that basal
synaptic transmission is reduced by 30% and that transmission amplitude, fidelity, and fatigue
resistance properties are reduced at elevated stimulation frequencies and in low external [Ca2+].
Moreover, transmission augmentation and post-tetanic potentiation (PTP) are disrupted in the mutant.
These results suggest that Leonardo plays a role in the regulation of synaptic vesicle dynamics, a
function which may underlie synaptic modulation properties enabling learning (Broadie, 1997).
14-3-3 proteins have been shown to interact with Raf-1 and cause its activation when
overexpressed. However, their precise role in Raf-1 activation is still enigmatic, as
they are ubiquitously present in cells and found to associate with Raf-1 in vivo
regardless of Raf's activation state. The function of the Drosophila
14-3-3 gene leonardo (leo) has been analyzed in the Torso (Tor) receptor tyrosine kinase (RTK)
pathway. In the syncytial blastoderm embryo, activation of Tor triggers the
Ras/Raf/MEK pathway that controls the transcription of tailless (tll). In
the absence of Tor, overexpression of leo is sufficient to activate tll expression. The
effect of leo requires D-Raf and Ras1 activities but not KSR or DOS, two recently
identified essential components of Drosophila RTK signaling pathways. Tor signaling
is impaired in embryos derived from females lacking maternal expression of leo. It is
proposed that binding to 14-3-3zeta/Leonardo by Raf is necessary but not sufficient for the activation
of Raf and that overexpressed Drosophila 14-3-3zeta requires Ras1 to activate D-Raf (Li, 1997).
Studies of Drosophila and other insects have indicated an essential role for the mushroom bodies in learning and memory. The leonardo gene encodes a Drosophila protein highly homologous to the vertebrate 14-3-3 zeta isoform. The gene is expressed abundantly and preferentially in mushroom body neurons. Mutant alleles that reduce Leonardo protein levels in the mushroom bodies significantly decrease the capacity for olfactory learning, but do not affect sensory modalities or brain neuroanatomy that are requisite for conditioning. These results establish a biological role for 14-3-3 proteins in mushroom body‚mediated learning and memory processes, and suggest that proteins known to interact with them, such as RAF-1 or other protein kinases, may also have this biological function (Skoulakis, 1996).
Leonardo exhibits similar involvement in the Raf/Ras pathway. Clones of mutant leonardo show a loss of photoreceptors. Ommatidia lack outer as well as inner photoreceptors. This phenotype is reminiscent of clones homozygous for Drosophila ras or raf hypomorphic alleles. Artificial activation of Raf rescues the nonviability causes by leonardo mutation and permits photoreceptor development. It is concluded that leonardo acts downstream of Ras and upstream of Raf in the signaling pathway that controls cell proliferation in the Drosophila eye imaginal disc (Kockel, 1997).
The reduction of leonardo gene dose appears to worsen the phenotype of 14-3-3eta mutants, suggesting that the different 14-3-3 proteins are partially redundant. However, reduction of leonardo gene does not detectably modify the rough eye phenotype caused by activated Ras1 expression (Chang, 1997).
Members of the ubiquitous 14-3-3 family of proteins are abundantly expressed in metazoan neurons. The Drosophila 14-3-3zeta gene leonardo is preferentially expressed in adult mushroom bodies, centers of insect learning and memory. Mutants
exhibit defects in olfactory learning and memory and physiological neuroplasticity at the neuromuscular junction. Because strong mutations in this gene are lethal, the nature of the defects that precipitate the learning and memory deficit and the role of the two protein isoforms encoded by leonardo in these processes were investigated. The behavioral deficit in the mutants is not caused by aberrant development, Leonardo protein is acutely required for learning and memory, and both protein isoforms can function equivalently in embryonic development and behavioral neuroplasticity (Philip, 2001).
The leonardo gene encodes three size classes of
transcripts attributable to use of alternative promoters and three
polyadenylation sites. Alternative splicing of exon 6 or 6' into the mRNA results in two protein isoforms (LeoI and LeoII) that differ by five amino acids. Because exons 6 and 6' are similar in size, alternative inclusion into the mRNA does not contribute to size heterogeneity. RT-PCR was used to determine the spatial and temporal expression of mRNAs that contain exon 6 (leoI) and 6' (leoII) (Philip, 2001).
Both leoI and leoII transcripts are present in embryos before activation of the zygotic genome, suggesting that they are deposited in the oocytes maternally. Exclusive presence of leoII transcripts in stage 10-12
embryos indicates preferential splicing of exon 6' into the mRNA, which
may underlie a specific contribution of LeoII to early development. In
contrast, both leoI and leoII transcripts are found in late embryos and all larval stages. In adult animals, although both isoforms are present in heads and abdomens, leoI is absent from the thorax (Philip, 2001).
To determine whether head tissues that require leo function
exhibit differential isoform expression, flies carrying the eyes-absent
mutation and wild-type animals were subjected to mushroom body ablation with
hydroxyurea. Lack of eye tissues does not
eliminate one of the isoforms differentially, but leoII is
specifically absent from the brains of mushroom body-ablated animals.
The results indicate that leoII transcripts are specific to
the mushroom bodies, whereas although leoI may be present in these neurons, it is more broadly expressed in the brain. Outside the
mushroom bodies, Leo protein is preferentially distributed in the
ellipsoid body neurons of the central complex. Because ellipsoid body neurons are not ablated by hydroxyurea and retain Leo immunoreactivity, they must contain only leoI transcripts. Presence of D14-3-3epsilon in all tissues and
stages tested suggests a broad role in basic cellular functions, and
possible colocalization with Leo isoforms may result in heterodimer
formation. Together, the differential expression of the two
leonardo mRNAs in embryos and adult tissues suggests
functional differences between the two Leo protein isoforms. Therefore,
a functional investigation of potential differences between LeoI and
LeoII isoforms was necessary before experiments aimed at rescuing the
learning-memory deficit of leo mutations (Philip, 2001).
To investigate potential functional differences of the putative
Leo isoforms, conditional rescue of lethality associated
with strong leo alleles was attempted. The level of Leo
protein induced in heads of rescued leoP1375 homozygotes was estimated. These homozygotes contained ~75%-80%
the amount of Leo present in similarly treated wild-type animals.
Because both LeoI and LeoII can support development to adulthood, under the conditions used the isoforms do not exhibit functional specificity. Furthermore, both LI and LII transgenes are highly inducible and allow manipulation of Leo
levels in adult heads over a wide range, and animals thus obtained do
not exhibit morphological defects. In addition, these experiments
identified highly inducible leo transgenes and methods to
obtain animals for behavioral testing (Philip, 2001).
The differential distribution of leo transcripts in adult heads suggested potentially differential roles for LeoI and LeoII in olfactory learning and memory. To investigate whether the behavioral deficit of leonardo viable alleles could be reversed by conditional induction of the leo transgenes, both transgenes were introduced into
Df(1)yw67c23;leo23,
(leo23) and Df(1)yw67c23;leoX1,
(leoX1) flies. To ascertain that the transgenes remained inactive during development, all animals including the Df(1)yw67c23 (yw) control strains were raised at 18°C. Because leonardo expression in tissues other than the mushroom bodies and ellipsoid body appears normal in these alleles, quantitative Western blots were not used to monitor Leo levels in the heads of these animals. Transgene induction in animals raised at 18°C was achieved by two 30 min heat shocks delivered 6 hr apart, followed by a 5-6 hr rest period. Accumulation of LeoI and LeoII in the mushroom bodies of leo23;LI and leo23;LII animals after the rest period was monitored by immunohistochemistry using the anti-Leo antibody. Very low levels of Leo protein are present in the mushroom bodies of leo23;LI and leo23;LII animals. A significant increase of both protein isoforms in the mushroom bodies and ellipsoid body neurons was observed during induction of the respective transgenes, although final accumulation did not equal the amount of Leo in controls. Similar results were obtained with leoX1;LI and leoX1;LII animals. Moreover, lack of Leo during development did not precipitate neuroanatomical aberrations in the brains of mutant animals raised at 18°C (Philip, 2001).
Animals raised at 18°C and ones subjected to the induction and rest
period were transferred to 23-24°C 2 hr before behavioral experiments. The growth conditions and temperature shift did not affect
the ability of the mutants to perceive the stimuli used for olfactory
conditioning compared with similarly treated controls. To further
investigate their olfactory acuity, the performance of mutants and
controls toward an attractive odor, geraniol, was measured using a
modified olfactory trap assay. Although an attractive odor is not used in conditioning, this test is a good measure of olfactory acuity. Flies seek and navigate toward the source of an attractive odor, a more complex olfactory task than simple avoidance of an aversive odor. The performance of experimental animals was not significantly different from controls. Performance of the animals after olfactory conditioning was assessed immediately after training or 90 min later to investigate memory. The performance of leo23;LI,
leo23;LII, leoX1;LI, and
leoX1;LII animals exhibited a significant
30% decrement compared with controls both immediately and 90 min after
training, similar to the decrement observed with
leo23 and leoX1 animals raised under similar
conditions. In contrast, learning and 90 min retention were not
significantly different from controls during transgene induction before
conditioning. The results suggest that LeoI and LeoII accumulation in
the mushroom bodies after transgene induction fully restores the
learning and memory deficit of leo23and
leoX1 mutants. Interestingly, under the
conditions used, both LeoI and LeoII isoforms appear equivalent in
rescuing the behavioral deficit of the mutants. Collectively, the
results indicate strongly that leonardo gene products are acutely required for mushroom body-dependent olfactory learning and memory (Philip, 2001).
Given the behavioral rescue of leo mutants, it was of interest to determine whether the learning and memory deficit exhibited by leo
viable alleles represents the maximal contribution of Leo-mediated
processes in mushroom body-dependent olfactory learning. The
ability to obtain animals that harbor very low levels of Leo throughout their heads was used to address this question. The nearly complete lack of Leo throughout the adult brain did not
result in neuroanatomical anomalies judged by histological and
immunohistochemical analyses using multiple markers to examine the morphology of the mushroom bodies and central brain (Philip, 2001).
To determine whether lack of Leo throughout these rescued animals precipitated general sensory deficits, they were subjected
to behavioral control tests. These leo mutants exhibited
normal attraction to geraniol, avoidance of electric shock (US), and
avoidance of both aversive odors (benzaldehyde and 3-octanol) used as
CS. However, all rescued animals exhibit a
25%-30% decrement in olfactory learning. Significantly, the decrease in learning
exhibited by the rescued lethal homozygotes and heteroallelics was
similar in magnitude with that of leo23;LI
animals. Therefore, near lack of Leo throughout the head does not
reduce learning further than exhibited by
leo23 animals, which lack Leo only in the
mushroom bodies. This suggests that the
leo23 and
leoX1 mutations represent strong mutant
alleles with respect to the behavioral phenotype. As with
leo23;LI animals, the learning deficit of
lethal homozygotes and heteroallelics was fully rescued to control
levels by multiple inductions of either LI or LI/LII transgenes. To
determine whether restoration of learning ability results from
permanent changes attributable to the elevation of Leo, animals were
kept at 18°C after induction and trained and tested along similarly
treated and aged controls. Restoration of learning during transgene
induction decayed back to mutant levels 60-70 hr later compared with
age-matched control animals (Philip, 2001).
These results indicate that induction of Leo to levels sufficient to
restore learning does not precipitate permanent changes but rather that
the available amount of protein is acutely essential for this process.
Furthermore, elevated Leo expression outside the mushroom bodies and
ellipsoid body observed in controls and abrogated in the mutants does
not appear essential for learning, the sensory inputs used in these
experiments, or for the neuroanatomical integrity of the brain (Philip, 2001).
Thus, acute induction of either LI or LII transgenes completely restores
learning and memory in leo23 and
leoX1 mutant flies. The behavioral
deficit in these animals is unlikely the result of sensory or
developmental defects below the threshold of detection but rather are
attributable to an acute requirement for Leo in learning-memory. This
conclusion is further supported by the reversible rescue of the
learning deficit exhibited by lethal homozygotes and heteroallelics. In
contrast to leo23 and
leoX1 mutants, which lack Leo in mushroom
body and ellipsoid body neurons, minimally rescued animals contain a negligible amount of Leo throughout their
heads. This lack of Leo in lethal homozygotes and heteroallelics should
exaggerate putative developmental or sensory deficits present in
leo23 and
leoX1. However, neither sensory deficits
nor anatomical aberrations were detectable in the later, despite the
lack of transgene induction in larval or pupal stages. Therefore,
either the 10%-15% residual Leo suffices for normal larval development
and the reorganization of the brain at pupariation or Leo isoforms are
not required for these processes. Because transgene induction and Leo
accumulation restores the learning deficit of the lethal alleles to
control levels, but this recovery is eliminated during the decay of the
protein, Leo is acutely necessary for learning (Philip, 2001).
Involvement of 14-3-3 proteins in multiple cellular processes may be at
least in part the result of multiple isotypes or isoforms present
within one cell. This may
be of particular importance in vertebrates in which nine isotypes
exhibit primarily overlapping expression patterns, especially in
neuronal tissues. Similarly, because Leo isoforms and D14-3-3epsilon
appear to be at least partially overlapping, heterodimerization among
the three 14-3-3 proteins is possible. In fact, genetic analysis
suggested interactions between leonardo and D14-3-3epsilon gene products critical to embryonic and eye development (Philip, 2001).
The distinct expression of leo transcripts in adult
ellipsoid body and thorax indicates that LeoI and LeoII may have
isoform-specific functions in these tissues and suggest that structural
differences between the two isoforms may be reflected in functional
specificity. The two Leo isoforms differ by five amino acids in the
variable sixth alpha helix. The first two unique amino acids in LeoII (K, N in place of Q, T) are never found at that position among metazoan 14-3-3 isotypes. The
third substitution (E in place of D) is present in the vertebrate zeta,
beta, tau, eta and sigma isotypes and the two Caenorhabditis
elegans isotypes. Finally, the last two amino acids (A, T in place
of S, G) are present in both yeast isotypes but not among animal 14-3-3s. Thus, the LeoII isoform appears to be a unique zeta isotype. Helix 6 does not appear to be involved in phosphopeptide binding or dimerization. It is unclear then whether the differences between LeoI and LeoII result in differential dimerization or substrate engagement. The mushroom bodies apparently contain both
LeoI and LeoII isoforms and the ellipsoid body contains only LeoI.
However, both isoforms rescue equally the olfactory learning and memory
deficits of leo mutants; thus, they do not appear to have
isoform-specific functions pertinent to these processes. Alternatively,
subtle functional differences may have been concealed by elevated
transgene expression and the accumulation of a single isoform in the
mushroom bodies (Philip, 2001).
Collectively, the data indicate that monomers and homodimers of either
Leo isoform and/or heterodimers with D14-3-3epsilon are capable of similar
physiological roles essential for learning and memory. The results
demonstrate that Leo proteins do not contribute to postembryonic developmental processes in the brain. This is expected to enable investigation and identification of signaling molecules engaged by each isoform in the adult mushroom body and ellipsoid body, which in turn may reveal functional differences among them. The role of Raf1 and the Ras/Raf cascade, which requires leonardo function for signaling in developmental processes, is of particular interest. Furthermore, these results establish an acute role for 14-3-3 proteins in behavioral neuroplasticity, and, by virtue of the high degree of conservation and similarly elevated neuronal expression, are directly applicable to 14-3-3 function in vertebrates (Philip, 2001).
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date revised: 15 August 2008
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