Neuron, Vol. 17, 27–41, July, 1996, Copyright 1996 by Cell Press
Control of Daughter Cell Fates during Asymmetric
Division: Interaction of Numb and Notch
Ming Guo, Lily Yeh Jan, and Yuh Nung Jan
Howard Hughes Medical Institute
and Departments of Physiology and Biochemistry
University of California, San Francisco
San Francisco, California 94143-0724
atonal,arefirstexpressed inclustersof ectodermalcells
to endow these cells with the competence to adopt
neuronal fates (reviewed by Ghysen and Dambly-Chau-
diere, 1988; Campuzano and Modolell, 1992). One sen-
sory organ precursor (SOP) is then singled out from
each cluster through a process of “mutual inhibition”
mediated by “neurogenic genes” including Notch and
Delta (reviewed by Campos-Ortega, 1988; Artavanis-
Tsakonas and Simpson, 1991; Ghysen et al., 1993). To
form an es organ, the SOP gives rise to two distinct
daughter cells, IIa and IIb (see Figure 3A). The IIa cell
then divides to produce the hair cell (tricogen) and the
socket cell (tormogen), the outer support cells. Shortly
and the sheath cell (thecogen), the inner cells (Bate,
1978; Hartenstein and Posakony, 1989). A different se-
ries of asymmetric divisions allows the SOP of a cho
organ (see Figure 3D) to give rise to the neuron and
three different support cells (the sheath cell, the cap
and Bodmer, 1995).
Notchand Deltahave beenshown tomediate cell–cell
communication in eye development (Cagan and Ready,
1989), muscle development (Corbin et al.,1991), oogen-
esis (Ruoholaet al.,1991; Xuetal.,1992), and neurogen-
esis (Lehmann et al., 1983) in Drosophila. Homologs of
Notch and Delta have been characterized in various
species rangingfrom worm tohuman (reviewedby Arta-
vanis-Tsakonas et al., 1995). Notch encodes a trans-
membraneprotein with EGF-like repeatsin theextracel-
lular domain and tandem ankyrin repeats in the
intracellular domain (Wharton et al., 1985; Kidd et al.,
1986). The Notch product has been postulated to act
as a receptor, whereas the Delta gene product, another
transmembrane protein with EGF repeats (Vaessin et
al., 1987; Kopczynski et al., 1988), may function as a
ligand for the Notch receptor (Heitzler and Simpson,
1991; Rebay et al., 1991).
Cell–cell interaction is required not only for singling
out SOPs, butalso for theproper cell fate determination
of SOPprogeny,as indicated bystudiesof temperature-
sensitive alleles of Notch and Delta. Reduction of Notch
or Deltafunction duringSOP progenyformation inpupal
development causes an adult es organ (bristle) to con-
tain four neurons and no support cells (Hartenstein and
Posakony,1990; Parks and Muskavitch, 1993).A slightly
earlier temperature shift, presumably prior to IIa and IIb
division, leads to two neurons and two sheath cells in
Deltatsflies (Parks and Muskavitch, 1993). Thus, it was
postulated that Delta specifies four distinct progeny
cells in a stepwise fashion during the SOP division and
the IIb cell division (Parks and Muskavitch, 1993).
Besidescell–cell interaction,a cell-intrinsicfactor, the
numb gene product, is also essential for cell fate deter-
mination of SOP progeny. numb encodes a protein with
a motif called the phosphotyrosine-binding (PTB) do-
main (Kavanaugh and Williams, 1994) or phosphotyro-
sine interaction (PID) domain (Bork and Margolis, 1995).
Loss of numb function transforms the IIb cell into the
IIa cell during embryogenesis (Uemura et al., 1989), and
During development of the Drosophila peripheral ner-
vous system, a sensory organ precursor (SOP) cell
undergoesroundsofasymmetric divisionsto generate
four distinct cells of a sensory organ. Numb, a mem-
brane-associated protein, is asymmetrically segre-
gated into one daughter cell during SOP division and
acts as an inherited determinant of cell fate. Here, we
show that Notch, a transmembrane receptor mediat-
ing cell–cell communication, functions as a binary
switch in cell fate specification during asymmetric di-
esis. Moreover, numb negatively regulates Notch,
probably through direct protein–protein interaction
that requires the phosphotyrosine-binding (PTB) do-
main of Numb and either the RAM23 region or the
very C-terminal end of Notch. Notch then positively
regulates a transcription factor encoded by tramtrack
(ttk). This leads to Ttk expression in the daughter cell
that does not inherit Numb. Thus, the inherited deter-
minant Numb bestows a bias in the machinery for
cell–cell communication to allow the specification of
distinct daughter cell fates.
In asymmetricdivision, an important processinthe gen-
eration of cell diversity during development, a mother
cell produces two daughter cells that ultimately adopt
distinct fates. Two mechanisms may be responsible for
making the two daughter cells different. One, the cell-
intrinsic mechanism, involves an inherited determinant
that is asymmetrically segregated to one daughter cell
at the time of cell division. The other, the cell-extrinsic
mechanism,entailscommunication ofthedaughter cells
with each other or with surrounding cells (reviewed by
Horvitz and Herskowitz, 1992). In the Drosophila periph-
eral nervous system (PNS), both mechanisms are used
to generate the distinct cell types of a sensory organ
(Uemura et al., 1989; Hartenstein and Posakony, 1990;
Parks and Muskavitch, 1993; Rhyu et al., 1994). It thus
providesan opportunityto assesshow thesetwo mech-
ification during asymmetric divisions.
Two main types of sensory organs in the larval and
adult Drosophila PNS, the externalsense (es) organ and
chodotonal (cho) organ, are formed in a progressive
process during embryogenesis and pupal development
(Bodmer and Jan, 1987; Campos-Ortega and Harten-
stein, 1985; Ghysen et al.,1986). The “proneural genes,”
including those in the achaete–scute complex and
overexpression of numb results in reciprocal cell fate
transformation (Rhyuet al.,1994). Immunocytochemical
studies have shown that Numb is asymmetrically local-
ized to one pole of the SOP and segregated to one of
the daughter cells (Rhyu et al., 1994; Knoblich et al.,
1995). Thus, asymmetrically distributed Numb confers
distinctdaughtercell fates(Rhyuet al.,1994).Asymmet-
ric divisions of the SOP and its daughter cells that give
rise to the adult es organ (bristle) also depend on numb
function (Rhyu et al., 1994); the cell fate transformation
issimilartothephenotype causedbyreduction of Notch
function. Similarly, asymmetric division of the MP2 neu-
ral precursor in the central nervous system (CNS) de-
pends on asymmetric localization of Numb (Spana et
numb exerts its function at least in part via a down-
stream target gene called tramtrack (ttk) (Guo et al.,
1995). ttk encodes two zinc finger proteins due to alter-
native splicing (Harrison and Travers, 1990; Brown et
al., 1991; Read and Manley, 1992). The 69 kDa Ttk pro-
teinhasbeenshowntoact asatranscriptional repressor
intheprocessofsegmentation (Brown et al.,1991;Read
et al., 1992). Like numb, ttk acts as a genetic switch.
Loss of ttk function causes the SOP daughter cell IIa to
be transformed into IIb, a phenotype opposite to the
lossofnumb function phenotype.Overexpression of ttk,
on the other hand, results in the same cell fate transfor-
mation as does loss of numb function (Guo et al., 1995).
Genetic and immunocytochemical studies indicate that
ttk is negatively regulated by numb (Guo et al., 1995).
Several questions are raised by the dependence of
asymmetric division on a gene encoding a cell-intrinsic
determinant(Numb) as wellas genes such as Notch and
Delta, which mediatecell–cell interaction.How does the
information derived from cell-intrinsic signals interface
with signals arising from cell–cell interaction? How are
these different instructions to the two daughter cells
we firstshowthat Notchplays a critical role inasymmet-
ric divisions during embryogenesis. We then demon-
strate that genetically Notch is most likely negatively
regulated by numb, and biochemically Notch binds to
Numb. This direct protein–protein interaction requires
either the RAM23 region or the very C-terminal end of
Notch and the PTB domain of Numb. Finally, we have
identified ttk as a downstream target gene of Notch.
Takentogether, we proposethat Ttkactsasa readout to
integrate theinformationderived from both cell-intrinsic
mechanism and cell–cell communication; the inherited
determinant Numb sets up or biases the direction of
cell–cell interaction to allow the specification of distinct
daughter cell fates during asymmetric divisions.
Ghysen et al., 1993), the role of Notch in asymmetric
divisions of the SOP has only been examined in the
adult (Hartenstein and Posakony, 1990), but not in the
embryo.Hence,we characterized theembryonicpheno-
types due toreduction of Notch function or overexpres-
sion of Notch and showed that they corresponded to
reciprocal daughter cell fate transformations.
Elimination of Notch function throughout develop-
ment results in a significant overproduction of neuronal
precursors (Lehmann et al., 1983). The general disorga-
nization of the PNS in these null mutants, however,
makes it difficult to ascertain any cell fate alterations
within the lineage of a single sensory organ. To over-
come this difficulty, a temperature-sensitive allele of
Notch (Notchts) was used. Embryos of Notchtswere first
raised at the permissive temperature (18?C) to allow the
normal development of the embryo and then shifted to
the nonpermissive temperature (30?C) at certain devel-
opmental stages to disrupt the function of Notch (see
SOPs are singled out and then divide asymmetrically
during 4–7 hr of embryogenesis at 25?C (Bodmer et al.,
1989). Shifting Notchtsembryos to the nonpermissive
temperature at stages corresponding to 4–5 hr of em-
bryogenesis at 25?C resulted in significant overproduc-
tion of neuronsin mostembryos,as revealedbystaining
with a neuronal marker MAb22C10 (Zipursky et al.,
1984).Usinganti-Cutantibody,which recognizesall four
cells of the es organ (Blochlinger et al., 1990), we exam-
ined thesite of emergence of normally a single es organ
and found that the number of Cut-positive cells in-
creased by a factor of two to three (data not shown).
Thus, most likely supernumerary SOPs emerged from
the disruption of Notch function at this early stage due
to failure of singling out of SOPs.
WhenNotchtsembryoswere shiftedtothe nonpermis-
sive temperature at stages corresponding to 5–7 hr of
embryogenesis at25?C, we observed phenotypesof cell
fate transformation within bothes and cho lineages. We
focused our studies in the dorsal-most region of an
abdominal hemisegment, which normally harbors two
es organs, and doubly stained the embryos with anti-
Cut antibody and MAb22C10. In wild type, there are
eight Cut-positive cells and two MAb22C10-positive
neurons. Among younger embryos in a Notchtsembryo
collection, which would have their Notch function dis-
rupted at an earlier stage, some had ten to twelve Cut-
positivecells; mostof thesecellsexpressed MAb22C10.
The rest of the embryos had a complement of eight
Cut-positive cells, though up to six of these cells also
expressed MAb22C10. It thus appears that even after
the singling out of the SOPs, the number of neurons
within anesorganincreaseswith thedisruptionof Notch
function. Thiscould beinterpretedasa cellfatetransfor-
mation during asymmetric divisions of SOP, analogous
to what hasbeen observed in the adult bristle formation
(Hartenstein and Posakony, 1990).
To test this further, we doubly stained the Notchts
embryos with MAb22C10, a neuronal marker, and anti-
Prospero antibody, which labels the nuclei of sheath
cells in both es and cho organs (Vaessin et al., 1991).
We focused our studies on the older embryos in the
collection that would have their Notch function dis-
rupted at a later stage. In the wild-type embryo, the two
Reduction of Notch Function during SOP
Division Causes Support Cells to Be
Transformed into Neurons
Although there have been extensive studies of Notch
function in the process of lateral inhibition to single out
a neuronal precursor from a proneural cluster(Campos-
Ortega, 1988; Artavanis-Tsakonas and Simpson, 1991;
Interaction of Notch with numb
Figure 1. Reduction
Transforms Sheath Cells to Neurons
(A–D) Two simple es organs at the dorsal-
mostregion ofanabdominal segmentinwild-
type embryo. (A) A schematic drawing of the
two isolated es organs, with each circle rep-
resenting anindividualcell. Green circles cor-
respond to the MAb22C10 staining that rec-
ognizes the cytoplasm of neurons shown in
(B) and (D), whereas red dots correspond to
the anti-Prospero staining that labels the nu-
clei of sheath cells shown in (C) and (D). In
wild type, two neurons (B) (two arrows in [D])
and two sheath cells (C) can be observed
(bracket in [D]).
(E–G) In Notchts, four neurons ([E] and four
arows in [G]) can be detected without the
associated sheath cells ([F] and bracket
(H) Lateral region of an abdominal segment
where five cho organs are aligned side by
side. In this region, there are also other cells,
one v? cho organ and three es organs. Simi-
larly to (A), green circles and red dots corre-
spond to the MAb22C10 and anti-Prospero
staining respectively. she, sheath cell; neu,
neuron; lig, ligament cell; cap, cap cell.
(I–K) In wild type, five cho neurons (I and K)
have five sheath cells associated with them
(J and K).
(L–N) In Notchts, the number of MAb22C10-
positive neurons increases (L and N), while
the number of anti-Prospero positive sheath
cells decreases (M and N). Moreover, the
lent to that of the sheath cell reduction (N).
isolated dorsal-most es organs have two MAb22C10-
positive neurons and two Prospero-expressing sheath
cells (Figures 1A–1D). In contrast, the Notchtsembryos
contained four neurons without associated sheath cells
at the corresponding location (Figures 1E–1G), indicat-
ing that the sheath cells are transformed into neurons
(see Figure 3B).As expected from such a cell fatetrans-
formation, staining with anti-Cut antibody revealed four
stronglystaining cells(hairs or sockets)and fourweakly
staining cells(neurons or sheathcells) (data not shown).
neurons toProspero-positive sheath cellsin cho organs
wasobserved (Figures1L–1N). This cellfatetransforma-
tion from support cells to neurons in both es and cho
organs further substantiates the role of Notch in cell
fate specification during asymmetric divisions. These
embryonic phenotypes were then used to investigate
the epistatic genetic relationships between Notch and
ttk, as well as between Notch and numb (see below).
to that due to loss of Notch function during the process
of singling out of neuronal precursors, it is suggested
that the Notch intracellular domain corresponds to a
constitutively active form of the Notch receptor (Lieber
et al., 1993; Rebay et al., 1993; Struhl et al., 1993).
We used theUAS–GAL4 system(Brand and Perrimon,
1993) and studied the effect of overexpression of the
constitutively active form of Notch (NotchACT) (Doherty
et al., 1996) that contains a truncated Notch (with the
extracellular domain deleted but with the transmem-
ing SOP divisions. Transgenic flies carrying UAS–
NotchACTweremated to transgenicflies carrying a GAL4
enhancer–trap line, 1407 GAL4, which expresses the
reportergene inall neurons of the PNS (Luo etal., 1994).
The embryos carrying UAS–NotchACTas wellas the 1407
GAL4 line would then express NotchACTprimarily in neu-
rons. At the dorsal-most region of abdominal segments
of these embryos,anti-Cut staining showed theexpres-
sion pattern of four strongly stained and four weakly
stained cells in approximately 90% of the segments
(data not shown). Double labeling of both MAb22C10
and anti-Prospero, however, revealed a cell fate trans-
formation inat least one of these two es organsin about
30%–40%of theabdominal segments examined.A typi-
cal example is shown in Figures 2A–2C, in which the es
organ on the top contains two anti-Prospero-positive
cells but no neurons, suggestive of a transformation
Overexpression of Activated Notch Results
in the Reverse Cell Fate Transformation
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is ubiquitously overexpressed during the stage when
neuronalprecursors are singled out, there isa reduction
of neuronal precursors (Lieber et al., 1993; Rebay et al.,
1993; Struhl et al., 1993; Lyman and Yedvobnick, 1995;
Bang et al., 1995).Since these phenotypes are opposite
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