Am J Physiol Cell Physiol 305: C22–C23, 2013;
doi:10.1152/ajpcell.00126.2013.
Editorial Focus
An inversin convergence. Focus on “Inversin modulates the cortical actin
network during mitosis”
Michael J. Caplan
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
cystic disease (2). Planar cell polarity is profoundly influenced
by the noncanonical Wnt signaling pathway, whereas the
canonical Wnt signaling pathway drives proliferation. The
gene whose mutation is associated with nephronophthisis type
II encodes a protein known as inversin (6). Inversin appears to
act as a switch that both turns off the canonical Wnt pathway,
thus inhibiting proliferation, and activates the noncanonical
Wnt pathway to drive planar cell polarity processes (7). When
inversin expression is lost, the imbalance between the resultant
hyperproliferation and misorientation of mitotic axis might
account for cyst development.
Although inversin’s connection to these processes has been
established, much remains to be learned about the mechanisms
through which it influences mitosis and mitotic axis. Inversin
localizes to the cilium and to cell-adhesive junctions (5, 10),
and a growing literature suggests that the cilium plays a
central, if complex, role in planar cell polarity (8). The paper
by Werner et al. presents evidence supporting the surprising
and novel conclusion that inversin may serve to link mitotic
machinery to the actin cytoskeleton and, through this linkage,
influence mitotic orientation (11). The authors base their conclusions on examinations of inversin knockout mice and in-
Address for reprint requests and other correspondence: M. J. Caplan,
Department of Cellular and Molecular Physiology, Yale University School of
Medicine, P.O. Box 208026, New Haven, CT 06520-8026 (e-mail: michael.
[email protected]).
Fig. 1. Inversin (orange) integrates signals from the cilium (dashed arrow) and
communicates them (solid arrows) to the subcortical cytoskeleton (red and
blue), to the cytoskeletal elements that mediate cleavage of the nucleus (green),
and to the mitotic spindle so as to orient separation of chromatin (purple).
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MITOSIS HAS THE POTENTIAL to be both a creative and a profoundly disruptive phenomenon. When considered exclusively
in the context of its effects on absolute cell number, mitotic cell
division is obviously the means through which cells replicate
themselves, as a consequence of which they increase the size
and density of their population. When it occurs in the threedimensional setting of a highly structured tissue, however,
mitotic replication needs to detect and to obey complex local
spatial clues. Failure to recognize these clues and to respond to
their intrinsic instructions can result in the distortion or destruction of tissue architecture and, with it, tissue function.
The architect Louis Sullivan (who, for better or for worse,
invented the modern skyscraper at the turn of the previous
century) is credited with coining the phrase “form follows
function.” While Sullivan was no doubt referring to the design of
man-made edifices, his words are no less insightful when applied
to the realm of biological structure. Furthermore, at the risk of
offending physiologists seduced by the siren songs of other
organs, it can be argued that few tissues better exemplify Sullivan’s
dictum than does the kidney. Each of a kidney’s ⬃1,000,000
nephrons shares a loop structure and a pattern of axial differentiation that together constitute key determinants of its capacity to absorb and concentrate. When it occurs in the epithelial
cells of the kidney, mitosis must thus honor the nephron’s
layout and be oriented so as to maintain the nephron’s dimensions and design constraints. The study by Werner et al. (11) in
this issue of American Journal of Physiology-Cell Physiology
offers interesting new insights into the mechanisms employed
by renal epithelial cells to ensure that mitotic cell division does
not perturb the kidney’s exquisite design.
Genetic renal cystic diseases, such as dominant and recessive polycystic kidney disease and nephronophthisis, are examples of conditions in which the proliferation of renal tubule
epithelial cells is linked to the distortion of renal tubular
geometry (9, 12). One of the many signaling pathways that
appear to be disrupted in these conditions controls planar cell
polarity. When applied to epithelial cells, the term “polarity” is
often used with reference to the asymmetric distribution of
proteins and lipids among the apical and basolateral domains of
the plasma membrane (4). As their name implies, planar cell
polarity processes, instead, determine the lateral asymmetries
in epithelial cell design and differentiation (1). These processes
are extremely important in generating structures, such as
nephrons, in which the properties of cells vary dramatically
along the linear axis of the tubule. Planar cell polarity-linked
pathways appear to influence the orientation of the spindle axis
during mitotic cell division, and “off axis” mitosis might
account for cyst development in at least some models of renal
Editorial Focus
C23
through which the cilium transduces messages that are capable
of modulating mitosis, cell shape and tissue morphogenesis.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author.
AUTHOR CONTRIBUTIONS
M.J.C. drafted the manuscript; edited and revised the manuscript; approved
the final version of manuscript.
REFERENCES
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2. Fischer E, Legue E, Doyen A, Nato F, Nicolas JF, Torres V, Yaniv M,
Pontoglio M. Defective planar cell polarity in polycystic kidney disease.
Nat Genet 38: 21–23, 2006.
3. Morgan D, Goodship J, Essner JJ, Vogan KJ, Turnpenny L, Yost HJ,
Tabin CJ, Strachan T. The left-right determinant inversin has highly
conserved ankyrin repeat and IQ domains and interacts with calmodulin.
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4. Muth TR, Caplan MJ. Transport protein trafficking in polarized cells.
Annu Rev Cell Dev Biol 19: 333–366, 2003.
5. Nurnberger J, Bacallao RL, Phillips CL. Inversin forms a complex with
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6. Otto EA, Schermer B, Obara T, O’Toole JF, Hiller KS, Mueller AM,
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JA, Strachan T, Kispert A, Wolf MT, Gagnadoux MF, Nivet H,
Antignac C, Walz G, Drummond IA, Benzing T, Hildebrandt F.
Mutations in INVS encoding inversin cause nephronophthisis type 2,
linking renal cystic disease to the function of primary cilia and left-right
axis determination. Nat Genet 34: 413–420, 2003.
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Schermer B, Benzing T, Cabello OA, Jenny A, Mlodzik M, Polok B,
Driever W, Obara T, Walz G. Inversin, the gene product mutated in
nephronophthisis type II, functions as a molecular switch between Wnt
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8. Simons M, Walz G. Polycystic kidney disease: cell division without a
c(l)ue? Kidney Int 70: 854 –864, 2006.
9. Takiar V, Caplan MJ. Polycystic kidney disease: pathogenesis and
potential therapies. Biochim Biophys Acta 1812: 1337–1343, 2011.
10. Watanabe D, Saijoh Y, Nonaka S, Sasaki G, Ikawa Y, Yokoyama T,
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monocilia and other 9⫹0 cilia. Development 130: 1725–1734, 2003.
11. Werner ME, Ward HH, Phillips CL, Miller C, Gattone VH, Bacallao
RL. Inversin modulates the cortical actin network during mitosis. Am J
Physiol Cell Physiol (March 20, 2013). doi:10.1152/ajpcell.00279.2012.
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AJP-Cell Physiol • doi:10.1152/ajpcell.00126.2013 • www.ajpcell.org
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versin-deficient cell lines. They report that, in both systems,
inversin deficiency is associated with a dramatic increase in the
number of multinucleate cells. Inversin deficiency is also
associated with increased cell size, a failure to round up during
mitosis, and mis-localization of the mitotic spindle. In addition,
the authors note that inversin-deficient cells manifest substantial alterations in the distributions of components of the actin
cytoskeleton. Most notably, inversin-deficient cells exhibit
extensive filopodia that persist throughout mitosis. The authors
conclude that inversin plays an important role in organizing the
actin cytoskeleton and in positioning the mitotic spindle, perhaps by helping to connect it to the actin cytoskeleton. They
suggest that the actin cytoskeleton responds to inversin-dependent influences by integrating ciliary signaling, nuclear division, and cell-matrix adhesion, all of which contribute to the
planar cell polarity phenotype (Fig. 1).
As is the case for any interesting new discovery, this study
raises at least as many questions as it answers. Perhaps the
most straightforward of these relates to the nature of the
physical connection between inversin and the actin cytoskeleton. It will be important to determine how inversin communicates with cytoskeleton. Is this connection direct or indirect?
What are the partner proteins that mediate this linkage? What
domains of the inversin protein participate in the requisite
interactions? The inversin protein contains sixteen ankyrin
repeats as well as a lysine-rich domain and a calmodulinbinding site (3). Understanding how these or other domains
participate in inversin’s relationship with the actin cytoskeleton
will help to define how inversin can act as a switch or adaptor
that toggles between a number of related but disparate processes. Similarly, it will be important to determine whether the
relationship between inversin and the cytoskeleton is regulated.
Do factors that participate in controlling the cell cycle determine when and where this interaction is initiated? Do signals
received through the cilium help to coordinate this interaction
and to define its spatial influence? The study by Werner et al.
has illuminated a new and potentially exciting connection
between the cytoskeleton and a protein that is a critical component of the cilium’s influence on planar cell polarity (11).
Exploring the nature of this connection will doubtless lead to a
new and more thorough understanding of the mechanisms