Cell News 4/2014
14
regulation of genes involved in cell wall biosynthesis and are
partially regulated by Crz1 and its orthologues (Thewes, 2014).
However, for
Neurospora crassa
hyperbranching of the hyphae
could be explained by the loss of the apical Ca
2+
gradient, which
is important for the tip dominance (Prokisch et al., 1997). Also in
different
Fusarium
species Ca
2+
gradients are involved in hyphal
branching (Kim et al., 2012). It has been shown that different
Ca
2+
signatures are produced dependent on the age, the deve-
lopment, and differentiation of specific structures in a species-
specific manner (Kim et al., 2012). The impact of calcineurin in
these different processes has not been investigated yet but it is
plausible that the phosphatase plays a role in some (if not all) of
these processes. This will be an interesting new field to study if
calcineurin or other Ca
2+
-inducible proteins can sense different
Ca
2+
signatures.
Further defects of calcineurin mutants have been shown in co-
nidiation and sclerotial development of fungi. For
Aspergillus
fumigatus
it was shown that calcineurin mutants have decre-
ased conidium production (Steinbach et al., 2006) with altered
conidial morphology (Steinbach et al., 2006; da Silva Ferreira et
al., 2007). Abnormal conidia had no nucleus and did not germi-
nate although the microtubules are normal in the mutant (da
Silva Ferreira et al., 2007). Calcineurin mutants of the gray mold
fungus
Botrytis cinerea
and of the citrus pathogen
Alternaria
alternata
even failed to produce mature conidia (Harren et al.,
2012; Tsai and Chung, 2014). In the necrotrophic plant patho-
gen
Sclerotinia sclerotiorum
calcineurin is involved in sclerotial
development in a phase-specific manner (Harel et al., 2006).
Whereas sclerotial development was impaired at the prematu-
ration phase, germination of preformed sclerotia was increased
in calcineurin mutants.
This raises the question whether calcineurin is involved in dif-
ferent developmental processes in a species- and phase-specific
manner. Again, as it is known that Ca
2+
signatures vary in a
phase- and species-specific manner, it would be interesting to
investigate in the future if calcineurin (or other proteins) can
sense different signatures.
Calcineurin and development in
Dictyostelium
The social amoeba
Dictyostelium discoideum
is maybe one of
the best model organisms to study developmental processes.
Dictyostelium
has unique features like the vegetative life cycle
with unicellular amoebae and the social life cycle where up to
100.000 amoebae aggregate and differentiate into two major
cell types: stalk cells and spores (Chisholm and Firtel, 2004).
Also for
D. discoideum
it is assumed that calcium plays a ma-
jor role during stalk cell differentiation (Malchow et al., 1996;
Kubohara et al., 2007; Gross, 2009) leading to the hypothesis
that calcium signals during differentiation are transmitted via
calcineurin. Evidence for a participation of calcineurin in this
developmental process came from studies using calcineurin
inhibitors like CsA, FK506, or gossypol (Horn and Gross, 1996;
Weissenmayer et al., 2005). Furthermore, the expression of
genes encoding for the catalytic CNA- as well as for the regula-
tory CNB-subunit is developmentally regulated in
D. discoideum
(Dammann et al., 1996; Aichem and Mutzel, 2001). Classical
knockouts of the CNA- or CNB-gene failed in
Dictyostelium
pointing towards an essential role of calcineurin also during
vegetative growth of the amoebae (Boeckeler et al., 2006).
However, silencing of the expression of either CNA or CNB
leads to a loss of tip dominance and branching of the stalk in
D.
discoideum
(Boeckeler et al., 2006; Thewes et al., 2014). Like for
fungi and mammals the defects in proper stalk formation can
be only partially explained by mis-regulation of genes through
the NFAT-/Crz1-cascade (Thewes, 2014; Thewes et al., 2014),
indicating that also for
Dictyostelium
other, yet unknown, calci-
neurin targets have to be involved.
Conclusion
Calcium is one of the most important signalling molecules in
eukaryotes and calcineurin is one of the most important target
proteins for calcium ions. Therefore calcineurin is involved in a
plethora of cellular and developmental processes in higher and
lower eukaryotes. Beside species-specific functions of this phos-
phatase a couple of parallels exist between higher and lower
eukaryotes. The most striking parallel might be that calcineurin
is involved in the development of “filamentous structures” like
dendrites, blood vessels, or hyphae by regulating tip dominance
and branching. Impairment of calcineurin function leads to de-
velopmental defects, which are accompanied in many cases by
death of animals during embryogenesis or cell death. However,
recent studies show that some mammalian isoforms of calci-
neurin have very specific duties in an organ-dependent manner.
Furthermore, studies in higher and lower eukaryotes show that
the phosphatase acts also spatiotemporal. The function of the
different isoforms and the spatiotemporal action need more at-
tendance in future studies. A couple of target proteins of calci-
neurin have been identified (Li et al., 2011) but current research
still focuses mainly on NFAT/Crz1-orthologues. More research is
needed to elucidate the role of other calcineurin targets during
developmental processes.
The parallels between higher and lower eukaryotes concerning
the function of calcineurin during developmental processes
show that lower eukaryotes with simple developmental pro-
grams can be very helpful models to study the involvement of
calcineurin in detail.
Acknowledgements
The Freie Universität Berlin financially supported this work.
References
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