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Oh no, Notch again!
Jonas Frise
Â
n and Urban Lendahl*
Summary
The Notch receptor signaling pathway is important for
morphogenesis and development of many organs and
tissues in most if not all multicellular species. The
classical view holds that Notch signaling keeps cells in
an undifferentiated state. Recently, however, this notion
has been challenged in the nervous system by two sets
of observations: Notch plays an active role in the differen-
tiation of glial cells,
(1±4)
and Notch influences the length
and organisation of neuronal processes.
(5±7)
In this
review, we analyse these recent data and discuss how
Notch signaling may be able to perform such
quite different tasks during nervous system develop-
ment. BioEssays 23:3±7, 2001.
ß 2001 John Wiley & Sons, Inc.
Introduction
A Notch receptor is a single transmembrane protein with an
extracellular domain that recognises cell-bound ligands of the
DSL (Delta/Serrate/Lag2) type presented on neighbouring
cells. Activation of the Notch receptor requires at least three
proteolytic cleavages (Fig. 1A) (for review see Ref. 8). The first
cleavage of the Notch receptor occurs during intracellular
trafficking at the prospective extracellular side by a furin-like
convertase, to generate a bipartate Notch receptor.
(9,10)
Ligand interaction then induces a second extracellular cleav-
age, closer to the plasma membrane,
(11)
and this, in turn, leads
to a third cleavage in the transmembrane region near the
cytoplasmic side;
(12±15)
for review see Ref 8. As a conse-
quence of this, the intracellular domain is released from the
membrane and translocates to the nucleus to become ``the
business end'' of the molecule. In the nucleus, the intracellular
domain acts in conjunction with the DNA-binding protein CSL
to control expression of downstream genes, most prominently
the HES genes, which encode a set of basic helix-loop-helix
negative transcriptional regulators (Fig. 1A) (for review see
Ref. 16). Processing of the Notch receptor shows very
interesting similarities to the processing of amyloid precursor
protein (APP), which plays a critical role in early onset
Alzheimer's disease. First, the intramembraneous cleavage
of Notch and APP are both regulated by presenilins,
(17± 20)
for
review see Ref. 21. Second, TNFa converting enzyme (TACE)
can mediate the second extracellular cleavage in Notch
(11)
as
well as the a-secretase cleavage in the extracellular part of
APP. The sequential proteolytic cleavage at opposite sides
of the plasma membrane observed in Notch, APP and an
increasing number of other proteins is referred to as regulated
intramembrane proteolysis, or RIP.
(22)
Notch signaling requires cell±cell interaction and in many
situations its effects on cellular differentiation are mediated via
a mechanism called lateral specification (lateral inhibition). In
lateral specification, the cell taking on the primary differentia-
tion fate expresses the DSL ligand at high levels; this activates
the Notch signaling pathway in juxtaposed cells, which results
in these cells remaining undifferentiated or assuming a second
differentiation fate (Fig. 1B).
(23,24)
In the nervous system,
neurons and glial cells are generated from undifferentiated
stem cells.
(25)
Cells destined to become neurons express high
levels of DSL ligand, thus suppressing neurogenesis in the
neighbouring cells. This view of Notch as an inhibitor of
neurogenesis is based on a large body of work from Drosophila
neurogenesis, Xenopus primary neurogenesis and retinal
development (for reviews, see Refs 23,24 and references
therein). Recent data, however, show that the function of
Notch does not stop at these early cell fate decisions in the
nervous system. Rather, Notch signaling also appears to
control two other aspects of neural development: gliogenesis,
i.e. the differentiation of glial cells, and neurite arborisation, i.e.
the length and organisation of neuronal processes.
Notch and gliogenesis
The principal order of differentiation from stem cells in the
nervous system is that neurons mature first, followed by dif-
ferentiation of glial cells (for review see Ref. 26). As discussed
above, it is well established that Notch has a role in blocking
neurogenesis, and it has been assumed that this leads to
maintenance of cells in an undifferentiated, stem-cell-like
state. This notion is, however, rapidly changing and recent
data show that Notch signaling actively promotes differentia-
tion of various glial cell types.
(1± 4)
Although it has been
previously observed that Notch in some cases may allow
gliogenesis in addition to blocking neurogenesis,
(27±29)
the
novelty of these four reports lies in the more instructive roles
Notch appears to play in this process in vertebrates.
BioEssays 23:3±7, ß 2001 John Wiley & Sons, Inc. BioEssays 23.1 3
Department of Cell and Molecular Biology, Karolinska Institute,
Sweden.
Funding agencies: The Swedish Cancer Foundation, Barncancerfon-
den and The Karolinska Institute.
*Correspondence to: Urban Lendahl, Department of Cell and
Molecular Biology, Medical Nobel Institute, Karolinska Institute,
SE-171 77 Stockholm, Sweden. E-mail: Urban.Lendahl@cmb.ki.se
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