The Rockefeller University Press
J. Cell Biol. Vol. 199 No. 7 1023–1024
As every beginning student of histology learns, epithelial cells
can be classified by their shape: columnar cells are tall and nar-
row, and cuboidal cells are roughly as tall as they are wide,
whereas squamous cells are wide and flat. These polarized cells
have distinct apical surfaces (facing the outside world or lumen
of an internal cavity or tube), lateral surfaces (facing adjacent
cells), and basal surfaces (facing the underlying basement
membrane). The relative sizes of these surfaces differ in colum-
nar, cuboidal, and squamous cells. For instance, squamous cells
have large apical and basal surfaces but small lateral surfaces.
Columnar cells are opposite, with large lateral surfaces but
small apical and basal surfaces. Though we have learned a great
deal about how epithelial cells develop polarity and their three
surfaces, we know very little about how these relative surface
areas and the corresponding shapes of the cells are determined.
In this issue of The Journal of Cell Biology, Gomez et al. have
studied the morphogenesis of the follicular epithelium overly-
ing the Drosophila melanogaster ovary. They show that endo-
cytosis of the immunoglobulin superfamily cell–cell adhesion
protein Fasciclin 2 from the lateral surface is required for cuboi-
dal to squamous cell shape transition. The serine/threonine
kinase Tao promotes the removal of Fasciclin 2 from the lateral
surface and thereby causes the shortening of the lateral surface.
In short, Tao is rising as a regulator of cell height.
In the lateral surface, there are many cell adhesion mole-
cules, such as Fasciclin 2, which form homophilic interactions.
Fasciclin 2 was discovered as a molecule critical for growth
cone guidance and neural recognition in insects (Bastiani et al.,
1987; Harrelson and Goodman, 1988; Snow et al., 1988), and
its clustering, internalization, and integration into the synaptic
membrane are crucial for synapse remodeling and plasticity.
During oogenesis in Drosophila melanogaster, the cells in
the follicular epithelium of the ovary undergo a transition
from a cuboidal to a squamous shape. In this issue,
Gomez et al. (2012. J. Cell Biol. http://dx.doi.org/10
.1083/jcb.201207150) show that the kinase Tao promotes
the endocytosis of the cell adhesion molecule Fasciclin 2
from the lateral surface of the cell and is critical for the
cuboidal to squamous cell shape transition. Their results
indicate that Tao is rising as a regulator of cell height.
Correspondence to Keith E. Mostov: email@example.com
Later work showed that loss of Fasciclin 2 in Drosophila outer
border cells but not inner polar cells, both of which are derived
from the ovary follicular epithelium, is critical for timely de-
lamination from the epithelium during development (Szafranski
and Goode, 2004). However, how Fasciclin 2 is down-regulated
was a mystery until now.
Adherens junctions establish the first connections be-
tween two cells in a developing epithelium. In the Drosophila
ovary, adherens junctions are found in the apical region of the
lateral membrane and rely on DE-Cadherin for cell–cell adhe-
sion. The dynamic nature of adherens junctions is important
for epithelial establishment, maintenance, and remodeling. Both
the formation and integrity of adherens junctions are regu-
lated. In one case, Notch signaling disassembles the adherens
junctions of cells in the follicular epithelium, which are me-
chanically stretched by the growth of the underlying germline
cyst and thereby promotes the flattening of these epithelial
cells for proper oogenesis (Grammont, 2007). In another case,
Dpp signaling promotes epithelial cell growth in height in the
Drosophila wing disc. Dpp’s effect is mediated through remod-
eling of adherens junctions (Widmann and Dahmann, 2009).
The more basal portion of the lateral surface of the Dro-
sophila ovarian epithelium uses Fasciclin 2 for cell–cell adhe-
sion. Gomez et al. (2012) now show that Fasciclin 2–mediated
cell adhesion maintains the height of the cell, and its removal
from the lateral surface is critical for cuboidal to squamous
cell shape transition. Furthermore, the authors show that Tao is
the upstream trigger of this removal. Interestingly, removal of
Fasciclin 2 from the lateral surface is mediated by endocytosis,
using Rab5-containing vesicles.
Left unresolved are how Tao promotes endocytosis
of Fasciclin 2 and whether it is a general regulator of cell
height during epithelial morphogenesis in species other than
Drosophila. Tao is a member of the Sterile-20 subfamily of
serine/threonine kinases, and several seemingly unrelated func-
tions have been ascribed to it (Fig. 1). These include activation
of a stress-responsive p38 MAPK, phosphorylation of the kinase
Par-1, which regulates microtubule dynamics and cell polarity,
and activation of the Salvador–Warts–Hippo pathway involved
in proliferation control. Data provided by the authors suggest
Cell height: Tao rising
Liang Cai1 and Keith E. Mostov2,3,4
1State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai 200433, China
2Department of Anatomy, 3Department of Biochemistry and Biophysics, and 4Cardiovascular Research Institute, University of California, San Francisco,
San Francisco, CA 94143
© 2012 Cai and Mostov This article is distributed under the terms of an Attribution–
Noncommercial–Share Alike–No Mirror Sites license for the first six months after the pub-
lication date (see http://www.rupress.org/terms). After six months it is available under a
Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license,
as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
T H E J O U R N A L O F C E L L B I O L O G Y
JCB • VOLUME 199 • NUMBER 7 • 2012 1024
membrane remodeling? This might involve a mechanism simi-
lar to that used to regulate transcytosis from the lateral to the
apical surface. Identifying such a mechanism would deepen
our understanding of epithelial morphogenesis in general.
After years of studies of individual signaling pathways and
their functions, it is time to focus on the connections between
these pathways and the players that sit at the crossroads.
We would like to thank Hao Wu for critical reading of the manuscript.
We apologize for any omissions when citing relevant literature because
of space restrictions.
Work in K.E. Mostov’s laboratory is funded by National Institutes
of Health grants R01DK074398, R37AI25144, R01DK091530, and
P01AI53194. L. Cai was a fellow of the Jane Coffin Childs Memorial Fund
Submitted: 26 November 2012
Accepted: 4 December 2012
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that none of these previously known functions is involved in
Fasciclin 2 endocytosis. As Tao’s role in this endocytic process
is dependent on its kinase activity, most likely Tao phosphory-
lates a component of the endocytic machinery, though one or
more intermediate steps might also be involved.
Membrane traffic at the lateral surface has previously been
shown to affect cell height. Delivery of membrane proteins to
the lateral surface utilizes the exocyst, a complex involved in
docking exocytic vesicles. Overexpression of the Sec10 exocyst
subunit in MDCK cells causes an increase in cell height but
not width (Lipschutz et al., 2000). Synthesis of lateral proteins,
but not apical proteins, was increased at a posttranscriptional
level, suggesting a feedback between delivery of proteins to the
lateral surface and their synthesis (Lipschutz et al., 2003).
At least in mammalian epithelial cells, the lateral surface is
enriched in phosphatidylinositol-3,4,5-trisphosphate. Partial
inhibition of the synthesis of this lipid by chemical inhibitors
gave a dose-dependent reduction in cell height, suggesting that
the abundance of this lipid in the lateral surface is a determinant
of the size of that surface and thus of cell shape (Gassama-Diagne
et al., 2006).
One surprising observation made by Gomez et al. (2012) is
that the Tao mutant causes not only accumulation of Fasciclin 2
at the lateral surface but also concentration of DE-Cadherin,
-Catenin, Crumbs, Par-6, and atypical PKC in the apical
surface. Because their data suggest that most likely Tao only
promotes endocytosis of laterally localized Fasciclin 2, the
authors suggest that the concentration of apical proteins in the
Tao mutant is a by-product of failed apical surface expansion.
An interesting question raised is why the failure in shortening
of the lateral surface causes a failure in expansion of the apical
surface. Is there an upstream regulator that couples shortening
of one surface with expansion of another surface during plasma
Figure 1. The known functions of Tao. Hutchison et al. (1998) show that
Tao binds and activates MAPK kinase. Liu et al. (2010) show that Tao
leads to microtubule destabilization. Boggiano et al. (2011) and Poon
et al. (2011) show that Tao phosphorylates Hippo kinase. In this issue,
Gomez et al. (2012) show that Tao promotes Fasciclin 2 endocytosis. Tao
appears to function in very distinct processes. Finding their relationships
and the signaling complexes that spatially and/or temporally regulate Tao
functions are important next steps.