Cell News 3/2013
14
RESEARCH NEWS
inherited from the polarized single layer epithelium before the
onset of stratification. Par3 binds mInsc in the epidermis and
this likely drives the apical recruitment of the mammalian ho-
mologues of Pins and Mud, LGN and NuMA (Fig.2B). However,
differential localization of aPKC/Par localization alone is not
sufficient to drive ACD as aPKC/Par also show an apical localiza-
tion in cells that undergo symmetric divisions in the epidermis.
To examine whether aPKC
λ
regulates oriented cell division,
epidermal cell fate, stem cell behavior and tissue homeosta-
sis in the epidermal lineage we analyzed epidermal specific
aPKC
λ
knockout mice. Loss of aPKC
λ
strongly disturbs epider-
mal homeostasis, stem cell maintenance, hair follicle cycling
and lineage differentiation causing progressive morphological
changes in different epidermal compartments, e.g. hair follicle
and sebaceous glands. This is accompanied by a gradual loss of
quiescent bulge stem cells (Fig.3B) and a temporary increase in
different proliferating progenitors. This ultimately leads to loss
of proliferative potential, stem cell exhaustion, increased diffe-
rentiation, complete alopecia and premature skin aging. Unex-
pectedly, inactivation of aPKC
λ
increased asymmetric divisions,
known to promote differentiation, not only in the developing IFE
but also in other stem/progenitor compartments of the epider-
mis, including the bulge stem cell compartment (Fig.3C).
To examine whether loss of aPKC
λ
would alter the cell fate of
bulge hair follicle stem cells towards more committed proge-
nitors, thus explaining the increase in more committed proge-
nitors, we crossed aPKC
λ
fl/fl mice with Lgr5CreERT2eGFP mice
(Barker et al., 2007) and with Rosa26RLacZ Cre-reporter mice
(Soriano, 1999). At P21, when HFs are in telogen, Lgr5 is exclu-
sively expressed in the lower bulge and hair germ HFSCs and its
progeny only contribute to the lower part of the hair follicle but
not to the JZ, infundibulum and interfollicular epidermis (Jaks
et al., 2008). Upon tamoxifen-induced activation of Cre at P21,
control Lgr5-progeny were labeled by
β
-galactosidase and con-
tributed exclusively to the lower non-permanent part of control
hair follicles (Fig. 3D,E). In contrast, aPKC
λ
-/-/
β
-galactosidase
positive Lgr5-progeny were not only found in the lower HF, but
also in JZ, infundibulum, and IFE (Fig.3D). Thus, loss of aPKC
λ
is crucial for homeostasis of self-renewing stratifying epithelia,
regulation of cell fate and differentiation and maintenance of
epidermal bulge stem cells and epidermal progenitor cells likely
through its role in balancing symmetric and asymmetric division
(Fig.3F).
The mechanisms by which aPKC
λ
regulates the balance between
symmetric and asymmetric divisions are less clear. Whereas loss
of aPKCs resulted in random spindle orientation in C. elegans or
in vitro (Dard et al., 2009; St Johnston and Ahringer, 2010; Dur-
gan et al., 2011), in vivo epidermal loss of aPKC
λ
caused a shift
towards more ACDs. In contrast, in vivo knockdown of known
regulators of spindle orientation, such as NuMA or LGN, promo-
te SCDs in the developing interfollicular epidermis (Williams et
al., 2011). This suggests that aPKC
λ
does not directly interfere
with the machinery crucial for spindle orientation. In agree-
ment, the localization of NuMA was also not obviously altered
in asymmetrically dividing aPKC
λ
-/- keratinocytes at E16.5. As
keratinocytes still express aPKC
ζ
, albeit in low amounts, this
might be sufficient to drive spindle orientation in the absence
of aPKC
λ
. Together, our data identify aPKC
λ
as essential for ba-
lancing ACD/SCD, which likely controls cell fate in the epidermis
and suggest that aPKC may either actively inhibit ACDs or pro-
mote SCDs in the epidermis.
Concluding remarks
These data from stratifying epithelia reveal that the mamma-
lian aPKC/Par complex is not only a crucial regulator of simple
epithelial polarity but also controls stratifying epithelial barrier
function. In addition, there is a specific role for aPKC
λ
in regu-
lating mammalian epidermal cell fate choices, likely by cont-
rolling the balance between ACD and SCD. A central remaining
question is the identification of the physiological relevant sub-
strates by which mammalian aPKCs regulate epidermal barrier
function, cell fate, oriented cell division, stem cell dynamics and
thus skin morphogenesis and homeostasis.
Acknowledgements
The work on aPKC is done as part of a long-term collaboration
with Dr. Michael Leitges, Biotechnology Centre of Oslo, Univer-
sity of Oslo. Work in the Niessen laboratory is funded by the
DFG, SFB 829 and SFB832, Krebshilfe and Köln Fortune.
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