Cell News 01/2017
30
The novel centrosomal protein Akna, a regulator of
microtubule organizing activity, controls neurogenesis
Germán Camargo Ortega, Pia A Johansson, Sven Falk, Stanislav Vinopal, Kalina Draganova,
Kaviya Chinnappa, Anna Gavranovic, Juliane Merl-Pham, Arie Geerlof, Regina Feederle,
Camino De Juan Romero, Stefanie M. Hauck, Victor Borrell, Frank Bradke,
Michaela Wilsch-Bräuninger, Wieland Huttner and Magdalena Götz
Presenting author: Germán Camargo Ortega
Helmholtz Zentrum München, Ingolstädter Landstr. 1,
85764 Neuherberg
Understanding mechanisms regulating neural stem cell (NSC)
homeostasis and their fate commitment is fundamental for
their efficient manipulation and future usage in regenerative
medicine. To contribute to this goal, our laboratory interro-
gates novel neurogenic molecular pathways by identifying
common regulators in neural stem cells of the developing
and adult brain (Pinto et al., 2008, Mol Cell Neurosci; Becker-
vordersandforth et al., 2010, Cell Stem Cell). These studies have
proved successful for the identification of new factors essential
for embryonic and adult neurogenesis (Pinto et al., 2009, Nat
Neurosci; Stahl et al., 2013, Cell) and key in direct neuronal
reprogramming (Masserdotti et al., 2015, Cell Stem Cell).
Here we show the functional and molecular analysis of another
novel factor common to embryonic and adult neurogenesis,
called Akna. We demonstrate that Akna, previously annotated
as AT-hook transcription factor, is rather a centrosomal protein
located predominantly at the subdistal appendages regulat-
ing microtubule nucleation and anchoring. Akna expression
is higher in differentiating NSCs and their progeny, the basal
progenitors, than self-renewing NSCs and mature neurons.
Accordingly, in vivo knock-down and overexpression experi-
ments combined with live imaging demonstrate that reducing
Akna abolishes delamination, while its elevation results in very
fast delamination and differentiation. Akna overexpression also
retains cells at the place of highest expression, in the sub-
ventricular zone (SVZ), showing that it is essential for young
neurons leaving the SVZ to migrate into the neuronal layers.
Delamination of RGCs (the NSCs) from their apical anchoring
to become basal RGCs (bRGCs) is crucial for the generation
of the extended outer SVZ, a unique germinal layer present
in brains with expanded cerebral cortex size and spatially
correlated with the stereotypic formation of cortical folds
(Martínez-Martinez et al., 2016, Nat Commun). Accordingly,
we found highest Akna mRNA levels in the VZ of ferret at the
critical time window for RGC delamination into bRGC and
OSVZ formation. In support of Akna being relevant for human
cerebral cortex expansion and folding, human Akna protein is
also localized at the centrosome and Akna mRNA is expressed
in the human fetal forebrain in a modular pattern along the
VZ, similar to other genes involved in gyrification (de Juan
Romero et al., 2015, EMBO J). At a functional level, Akna over-
expression in human cerebral organoids mediated delamination
of NSCs. Thus, the central role of Akna in NSC biology and
cortical development seems to be conserved between mouse,
ferret and human. We identified a novel centrosomal protein
with heterogeneous expression in stem cell subtypes mediat-
ing the epithelial-mesenchymal transition-like process of NSC
delamination and differentiation in neurogenesis.
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