Asymmetric segregation of Numb: a mechanism for neural
specification from Drosophila to mammals
Michel Cayouette & Martin Raff
Nature Neuroscience 5, 1265 - 1269 (2002)
doi:10.1038/nn1202-1265
doi:10.1038/nn1202-1265
December 2002 Volume 5 Number 12 pp 1265 - 1269
Asymmetric segregation of Numb: a
mechanism for neural specification from
Drosophila to mammals
Michel Cayouette1, 2 & Martin Raff1
1. MRC Laboratory for Molecular Cell Biology and Cell Biology Unit,
University College London, Gower Street, London WC1E 6BT, UK
2. Present address: Stanford University, Department of Neurobiology,
Fairchild Building, 299 Campus Drive, D231, Stanford, California 943055125, USA
Correspondence should be addressed to M Cayouette. e-mail:
m.cayouette@stanford.edu
It is a major challenge to understand how the neuroepithelial
cells of the developing CNS choose between alternative cell fates
to generate cell diversity. In invertebrates such as Drosophila
melanogaster and Caenorhabditis elegans, asymmetric
segregation of cell-fate determining proteins or mRNAs to the
two daughter cells during precursor cell division plays a crucial
part in cell diversification. There is increasing evidence that this
mechanism also operates in vertebrate neural development and
that Numb proteins, which function as cell-fate determinants
during Drosophila development, may also function in this way in
vertebrates. Recent studies on mouse cortical progenitor cells
have provided the strongest evidence yet that this is the case.
Here, we review these and other findings that suggest an
important role for the asymmetric segregation of Numb proteins
in vertebrate neural development.
The mammalian brain contains hundreds of cell types that develop from
neuroepithelial cells that initially all look alike. It is still uncertain to
what extent asymmetric cell division of neuroepithelial cells contributes
to this cell diversification process. The term 'asymmetric cell division' is
often used to describe any division in which the two daughter cells adopt
different fates1. Because identical daughter cells of a symmetric division
could be induced to adopt different fates as a result of their exposure to
different extracellular signals, we use the term asymmetric cell division
in its more restricted sense, to mean a division in which the two
daughter cells inherit different cell-fate determinants from the mother
cell.
We begin by briefly reviewing the key findings in Drosophila, where the
asymmetric segregation of cell-fate determinants is known to be crucial
for neural cell diversification2, 3. These findings provide a framework for
considering the evidence that similar mechanisms operate in
vertebrates.
Asymmetric segregation of Numb in Drosophila
Our understanding of the molecular basis of asymmetric cell divisions in
animal development has come mainly from studies in C. elegans and
Drosophila. In Drosophila, asymmetric segregation of the Numb protein
influences cell-fate choice in both neural and non-neural development4-9.
Numb is a plasma membrane–associated cytoplasmic protein that
contains a phosphotyrosine-binding (PTB) domain and antagonizes
Notch signaling10-12. Numb is thought to become associated with the
plasma membrane through phosphotyrosine binding, and in mammalian
cells, there is evidence that different PTB domain isoforms may regulate
the subcellular localization of Numb proteins13. In the Drosophila
peripheral nervous system, each external sensory organ develops from
a single sensory organ precursor (SOP) cell that produces the four cells
that form the organ. In the first division of the SOP cell, Numb localizes
asymmetrically at one pole of the mitotic cell cortex. It overlies one pole
of the mitotic spindle so that only one daughter cell inherits the protein.
As a result, this daughter becomes a IIb cell, whereas the other
becomes a IIa cell6. These two cells then divide to produce the different
cell types of the sensory organ (Fig. 1a). In Numb-deficient mutants,
the first SOP division produces two IIa cells (Fig. 1b), whereas if Numb
is overexpressed, this division produces two IIb cells (Fig. 1c). These
results suggest that Numb promotes the IIb cell fate.
A good deal is known about the molecular machinery that localizes and
segregates Numb and how Numb influences cell fate in Drosophila (for
review, see refs. 2,3,14). In Drosophila neural precursors, for example,
the Inscuteable protein localizes asymmetrically to the apical cortex
before mitosis and directs mitotic spindle orientation and the
segregation of Numb to the basal daughter cell. In SOP cells, Numb
influences cell fate by repressing Notch signaling, although in other
cases its mechanism of action is unclear. In general, it seems that that
the primary function of Numb is not to specify a particular cell fate, but
rather to create two daughter cells that can respond differently to
environmental cues.
Plane of cell division and cell-fate choice in vertebrates
The neuroepithelial cells of the developing vertebrate CNS function as
neural progenitor cells. They divide extensively and produce a large
variety of cell types. The type of cells they produce and the rate at
which they produce them change as development proceeds. Early on,
cell divisions are largely proliferative, each producing two neuroepithelial
cells. Later, most cell divisions are differentiative, each producing either
one daughter that differentiates and one that remains a neuroepithelial
cell, or two daughters that differentiate. The early differentiative
divisions produce neurons, and the later ones produce glial cells or their
precursors.
Although in Drosophila the orientation of cell division plays a critical part
in segregating cell-fate determinants, and thereby in cell-fate choices, it
is less clear if the plane of neuroepithelial cell division influences cell fate
choices in vertebrates. The first direct evidence that the plane of
neuroepithelial cell division changes with development and may
influence cell fate came from pioneering studies by Chenn and
McConnell15. They used videomicroscopy to follow cell divisions in the
ventricular zone of explants of developing ferret cortex. They found that
early in development, most cells divide with their mitotic spindle aligned
horizontally to the plane of the neuroepithelium, and later in
development, more cells divide with their mitotic spindle aligned
vertically to the plane of the neuroepithelium. As their name suggests,
neuroepithelial cells have some epithelial cell characteristics, including
apical–basal polarity and molecularly distinct apical and basolateral
plasma membrane domains. Thus, neuroepithelial cells that divide with
a horizontal spindle are likely to distribute both apical and basolateral
components equally to their daughter cells, whereas the cells that divide
with a vertical spindle are likely to distribute apical components
preferentially to the apical daughter cell (Fig. 2). Indeed, there is
molecular evidence that the divisions with a vertical spindle are
asymmetric, in that an unidentified antigen recognized by anti-Notch1
antibodies segregates exclusively to the basal daughter cell15.
The Chenn and McConnell study15 also suggests that the plane of
neuroepithelial cell division can influence the fate of the two daughter
cells, raising the possibility that asymmetric segregation of cell-fate
determinants might contribute to cell diversification. In the developing
cortical neuroepithelium, most daughter cells either stay in the
epithelium and divide again, or migrate away and differentiate. Using
videomicroscopy of cortical slices, Chenn and McConnell found that in
divisions with a horizontal spindle, both daughter cells tend to stay in
the neuroepithelium, suggesting that they remain neuroepithelial cells.
In divisions with a vertical spindle, by contrast, the basal daughter cell
tends to migrate away, suggesting that it committed to differentiation;
the apical daughter of such divisions tends to stay in the epithelium,
suggesting that it remains a neuroepithelial cell. Somewhat later in
development, it is likely that many neuroepithelial divisions produce two
daughter cells that commit to differentiation, but such divisions were not
included in that study, and it remains unknown whether they occur with
a horizontal or vertical spindle.
Some neuroepithelial cells in the developing rat retina also divide with a
vertical spindle16. In recent timelapse videomicroscopy experiments in
newborn rat retinal explants, we found that the two daughter cells of
divisions with a horizontal spindle tend to become the same cell type,
whereas the two daughter cells of divisions with a vertical spindle tend
to produce daughters that become different (M.C. and M.R., unpub.
data). Thus, the plane of cell division can apparently influence cell-fate
choice in the retina, as well as in the cortex. In both cases, it is likely to
do so through the asymmetric segregation of cell-fate determinants (see
below).
In Drosophila, cell-fate determinants such as Numb can be
asymmetrically segregated either along the apico–basal axis of a
dividing epithelial cell (in divisions with a vertical spindle) or
perpendicular to this axis—in the plane of the epithelium (in divisions
with a horizontal spindle)17. In principle, therefore, divisions with a
horizontal spindle could also segregate cell-fate determinants
asymmetrically in vertebrate neuroepithelia, as suggested by others18,
but this remains to be shown.
Asymmetric segregation of mammalian Numb
Two groups independently identified a mammalian homolog of
Drosophila Numb (m-Numb)19, 20. The m-Numb protein is located at the
apical cortex of mitotic neuroepithelial cells in both the developing
mouse cortex and rat retina16, 20. Thus, when a neuroepithelial cell
divides with a vertical spindle, only the apical daughter cell inherits m-
Numb, whereas when it divides with a horizontal spindle, both daughter
cells inherit m-Numb.
As m-Numb is localized apically in mitotic mouse cortical neuroepithelial
cells, and the apical daughter of divisions with a vertical spindle tends to
remain a neuroepithelial cell15, it has been suggested that early in
development, m-Numb acts to inhibit the differentiation of the
neuroepithelial cells21. At later stages, however, it seems to be
permissive for neuronal differentiation. As we discuss later, another
mouse homologue of Numb called Numblike seems to act redundantly
with Numb in mouse neurogenesis. Although Numblike is a cytoplasmic
protein in Drosophila and distributes symmetrically in neuroblasts, the
level of Numblike in vertebrate neuroepithelial cells is too low to be sure
of its subcellular localization22.
A Numb homologue has also been identified in chickens23. Surprisingly,
it localizes basally rather than apically in dividing avian neuroepithelial
cells. Thus, chicken Numb would be segregated to the basal daughter
rather than the apical daughter when a neuroepithelial cell divides with
a vertical spindle. The significance of this difference between
mammalian and chicken Numb distribution remains unknown.
Effects of altering Numb expression
To help determine the function of Numb proteins in vertebrate neural
development, both gain-of-function and loss-of-function experiments
have been done. Expression of an m-numb transgene in mammalian
neural cell lines was found to be permissive for neuronal
differentiation24, whereas in similar experiments in chick neuroepithelial
cells in vivo, it was found to allow neuronal differentiation in some cells
but to inhibit differentiation and promote proliferation in others23. The
simplest interpretation of these findings is that Numb overexpression
has different effects on neuroepithelial cells at different stages of
maturation, as we discuss later.
Two groups independently generated m-numb knockout mice, which die
around E11.5 with CNS abnormalities. One group found that cells
expressing neuronal markers appear earlier in the m-numb mutant
forebrain than in wild-type forebrain21, consistent with the possibility
that m-numb can normally suppress neuronal differentiation. A second
group25, by contrast, found a delay in neuronal differentiation in the
hindbrain of m-numb mutants compared to wild type, consistent with
the possibility that m-numb can be permissive for neuronal
differentiation. The significance of these contradicting results remains
unexplained, but recent double-knockout experiments provide some
clarification about the role of m-Numb in early CNS development22.
Although numblike knockout mice appear normal, conditional
inactivation of m-numb in neuroepithelial cells in numblike-deficient
mice gives a much more severe CNS phenotype than that seen in mnumb knockout mice, with a dramatic decrease in neuroepithelial cells22
(Y. N. Jan, pers. comm.). These findings suggest that m-Numb and
Numblike may cooperate to promote neuroepithelial cell self-renewal in
early neurogenesis.
Taken together, these findings indicate that Numb proteins are essential
in vertebrate neural development, but they do not indicate whether the
asymmetric segregation of these proteins at mitosis influences the fate
of the two daughter cells.
Segregation of Numb and vertebrate cell fate
It has recently been shown that the asymmetric segregation of m-Numb
can influence the developmental fate of daughter cells26. This study used
a powerful clonal culture system in which the development of isolated
embryonic mouse cortical neuroepithelial cells in microwells can be
followed by videomicroscopy. Previously, by recording each cell division
and then staining the differentiated cells with antibodies to identify the
cell types to which the divisions gave rise, these investigators were able
to reconstruct the cell lineage trees that revealed some common
patterns of cell division and differentiation27, 28. As found in vivo,
neurons developed before glial cells, and some divisions produced
daughter cells that developed similarly, whereas others produced
daughters that developed differently. Because the environment was
relatively uniform in these cultures and the cells could not contact cells
outside their own clone, it seems likely that these differences in
behavior reflect intrinsic differences between the neuroepithelial cells.
In more recent experiments, these investigators focused on pairs of
daughter cells that originated from a single neuroepithelial cell in
culture26. Using immunostaining to detect m-Numb, they found that
about 30–40% of such daughter cells segregate m-Numb
asymmetrically into one of the two daughter cells. Thus, as previously
reported in retinal neuroepithelial cells16, dissociated cortical
neuroepithelial cells can segregate m-Numb asymmetrically when they
divide in culture. Most importantly, they found that the asymmetric
distribution of Numb correlates with the fate of the daughter cells. Using
antibodies to identify neurons, they observed three types of cell
divisions: those that produced two neuroepithelial (progenitor) cells
(P/P), those that produced two neurons (N/N) and those that produced
a neuroepithelial cell and a neuron (P/N). Using double-staining
experiments, in which pairs of daughter cells were stained for both mNumb and a neuronal marker, they found that in more than 80% of the
P/N divisions, m-Numb is distributed asymmetrically, whereas in 80–
90% of the N/N divisions, m-Numb is distributed symmetrically. Thus,
when m-Numb is distributed asymmetrically between daughter cells, the
daughters usually have different fates (P/N); when m-Numb is
distributed symmetrically, the daughters usually have the same fate
(N/N).
These findings raise the possibility that m-Numb directly influences cellfate choice. To test this possibility further, this group compared the
behavior of cortical progenitor cells from m-numb knockout mice with
those from wild-type littermates26. Although Numblike was presumably
still present in these cells, they found that in the m-Numb-deficient
cells, the proportion of P/N divisions was decreased and the proportion
of P/P divisions was increased. The proportion of N/N divisions,
however, remained unchanged. This finding suggests that, without mNumb, neuroepithelial cells are less able to produce two different
daughter cells, consistent with the possibility that m-Numb influences
asymmetric cell-fate decisions.
Is the daughter cell that inherits m-Numb in an asymmetric cell division
more or less likely to become a neuron? In E10 cells, the m-Numbcontaining daughter cell in P/N cell pairs is about equally likely to be a
neuroepithelial cell or a neuron. By contrast, in E14 cells, the m-Numbcontaining daughter cell in a P/N cell pair is usually the neuron. This is
another example of Numb proteins having different effects at different
stages of development. We return to this point below.
The influence of m-Numb in asymmetric cell divisions that produce two
neurons has also been studied26. In 92% of the N/N pairs with
asymmetric m-Numb distribution, the neurons had different
morphologies after 4 days in culture: the neuron that inherited m-Numb
usually had longer processes, raising the possibility that m-Numb may
also influence the subtype or morphology of neurons in N/N divisions.
Studies in the newborn rat retina also suggest that the asymmetric
segregation of m-Numb influences cell fate. As mentioned earlier, in
retinal neuroepithelial cells that divide with a vertical spindle, m-Numb
is inherited preferentially by the apical daughter cell15, and these
divisions produce daughter cells that tend to become different cell
types; in divisions with a horizontal spindle, both daughters inherit mNumb16 and tend to become the same cell type, usually photoreceptor
cells (M.C. & M.R., unpub. data). Moreover, overexpression of m-Numb
in dividing retinal neuroepithelial cells increases the development of
photoreceptor cells and decreases the number of non-photoreceptor
cells (M.C. & M.R., unpub. data). Thus, the asymmetric segregation of
m-Numb may contribute to cell diversification in a number of regions of
the CNS.
How do Numb proteins influence cell fate?
Numb proteins have been shown to inhibit Notch signaling in both
Drosophila and vertebrates, possibly by binding to the cytosolic tail of
transmembrane Notch10-12. Recent work by Knoblich and colleagues
suggests that Drosophila Numb inhibits Notch signaling by recruiting
alpha-Adaptin, which would be expected to stimulate the endocytosis of
Notch29. The same mechanism may operate in vertebrate cells, as mNumb is associated with clathrin-coated pits, vesicles and endosomes30.
These results also raise the interesting possibility that Numb proteins
might regulate the internalization of various receptors involved in cellfate decisions. Numb proteins also bind to other intracellular proteins
such as Siah-1 and LNX. These proteins can regulate Numb function, but
it is still unclear what roles they have in development31-34.
It is well known that Notch signaling has different effects at different
times in development35. Early in development, for example, Notch
mediates lateral inhibition, in which a differentiating cell inhibits its
neighbors from differentiating as well. Later in development, Notch
signaling may promote the differentiation of some cell types (for
example, refs. 36–38). Thus, even if Numb proteins act exclusively by
inhibiting Notch signaling, they would be expected to have different
effects at different times of development and in different circumstances.
In Drosophila, Numb acts at multiple stages in both the SOP and
neuroblast lineages: it initially helps daughter progenitor cells to adopt
different fates, and it later helps terminally differentiating cells to adopt
different fates. As mentioned earlier, overexpression of Numb in chick
neuroepithelial cells causes some cells to undergo premature
differentiation and others to delay differentiation and continue to
proliferate23. It is possible that these different responses reflect
differences in the maturation of the developing chick neuroepithelial
cells. In light of the results discussed above26, it seems that the effect of
Numb on mouse neuroepithelial cells also changes as development
progresses.
It has recently been found that m-Numb RNA can be alternatively
spliced to produce multiple m-Numb isoforms, which can have different
functions13, 24. There are at least four such isoforms in both humans and
mice. In a neural cell line and in primary neural crest stem cells, two mNumb isoforms promote differentiation, and two inhibit differentiation
and promote proliferation24. It is unclear if all of the isoforms can be
asymmetrically segregated during cell division or to what extent isoform
differences explain the different effects of m-Numb at different stages of
development. Studies with isoform-specific antibodies and knock-downs
will be required to clarify these issues.
What next?
Although asymmetric segregation of Numb proteins during cell division
seems to play a part in cell-fate choice in some parts of the developing
vertebrate nervous system, a number of questions remain. How
widespread is this function of Numb proteins in vertebrate development?
Does asymmetric segregation of cell-fate determinants have a role in
the developing spinal cord, for example, and in nonneural organs? This
seems likely, as in injured spinal cord and adult oesophageal epithelium,
stem cells can apparently re-orient their mitotic spindle and divide
asymmetrically39, 40. Besides Numb proteins, what other intracellular
cell-fate determinants segregate asymmetrically during cell division and
contribute to cell-fate choice in vertebrates? In Drosophila, proteins
such as Prospero, Staufen, Miranda and Partner of Numb also localize
asymmetrically at the basal cortex of the neuroblast and segregate
asymmetrically into one daughter cell. Homologs of some of these
proteins have been identified in vertebrates, but whether these or other
proteins have a role in vertebrate asymmetric cell divisions and cell-fate
determination remains to be determined. Can neuroepithelial cell
divisions with a horizontal spindle segregate cell-fate determinants
asymmetrically in vertebrates, as they can in Drosophila17, 41? How is the
mitotic spindle positioned by the cell to ensure the appropriate
segregation of cell-fate determinants, and what signals the cell to divide
asymmetrically in the first place? Some of these questions have been
partially answered in Drosophila, and history suggests that at least
some of the answers will also apply to vertebrates. The finding that
vertebrate cells in culture can segregate m-Numb asymmetrically when
they divide15, 25 should make it possible to use cell biological strategies
to study the molecular mechanisms involved in the segregation process.
Received 31 July 2002; Accepted 17 October 2002.
REFERENCES
1. Horvitz, H.R. & Herskowitz, I. Mechanisms of asymmetric cell division: two Bs
or not two Bs, that is the question. Cell 68, 237-255 (1992). | PubMed |
2. Knoblich, J.A. Asymmetric cell division during animal development. Nat. Rev.
Mol. Cell Biol. 2, 11-20 (2001). | Article | PubMed |
3. Lu, B., Jan, L. & Jan, Y.N. Control of cell divisions in the nervous system:
symmetry and asymmetry. Annu. Rev. Neurosci. 23, 531-556
(2000). | Article | PubMed |
4. Carmena, A., Murugasu-Oei, B., Menon, D., Jimenez, F. & Chia, W. Inscuteable
and numb mediate asymmetric muscle progenitor cell divisions during
Drosophila myogenesis. Genes Dev. 12, 304-315 (1998). | PubMed |
5. Knoblich, J.A., Jan, L.Y. & Jan, Y.N. Asymmetric segregation of Numb and
Prospero during cell division. Nature 377, 624-627 (1995). | PubMed |
6. Rhyu, M.S., Jan, L.Y. & Jan, Y.N. Asymmetric distribution of numb protein
during division of the sensory organ precursor cell confers distinct fates to
daughter cells. Cell 76, 477-491 (1994). | PubMed |
7. Spana, E.P., Kopczynski, C., Goodman, C.S. & Doe, C.Q. Asymmetric
localization of numb autonomously determines sibling neuron identity in the
Drosophila CNS. Development 121, 3489-3494 (1995). | PubMed |
8. Uemura, T., Shepherd, S., Ackerman, L., Jan, L.Y. & Jan, Y.N. numb, a gene
required in determination of cell fate during sensory organ formation in
Drosophila embryos. Cell 58, 349-360 (1989). | PubMed |
9. Wan, S., Cato, A.M. & Skaer, H. Multiple signalling pathways establish cell fate
and cell number in Drosophila malpighian tubules. Dev. Biol. 217, 153-165
(2000). | Article | PubMed |
10. Frise, E., Knoblich, J.A., Younger-Shepherd, S., Jan, L.Y. & Jan, Y.N. The
Drosophila Numb protein inhibits signaling of the Notch receptor during cell-cell
interaction in sensory organ lineage. Proc. Natl. Acad. Sci. USA 93, 1192511932 (1996). | Article | PubMed |
11. Guo, M., Jan, L.Y. & Jan, Y.N. Control of daughter cell fates during asymmetric
division: interaction of Numb and Notch. Neuron 17, 27-41 (1996). | PubMed |
12. Spana, E.P. & Doe, C.Q. Numb antagonizes Notch signaling to specify sibling
neuron cell fates. Neuron 17, 21-26 (1996). | PubMed |
13. Dho, S.E., French, M.B., Woods, S.A. & McGlade, C.J. Characterization of four
mammalian numb protein isoforms. Identification of cytoplasmic and
membrane-associated variants of the phosphotyrosine binding domain. J. Biol.
Chem. 274, 33097-33104 (1999). | Article | PubMed |
14. Schaefer, M. & Knoblich, J.A. Protein localization during asymmetric cell
division. Exp. Cell Res. 271, 66-74 (2001). | Article | PubMed |
15. Chenn, A. & McConnell, S.K. Cleavage orientation and the asymmetric
inheritance of Notch1 immunoreactivity in mammalian neurogenesis. Cell 82,
631-641 (1995). | PubMed |
16. Cayouette, M., Whitmore, A.V., Jeffery, G. & Raff, M. Asymmetric segregation
of Numb in retinal development and the influence of the pigmented epithelium.
J. Neurosci. 21, 5643-5651 (2001). | PubMed |
17. Roegiers, F., Younger-Shepherd, S., Jan, L.Y. & Jan, Y.N. Two types of
asymmetric divisions in the Drosophila sensory organ precursor cell lineage.
Nat. Cell Biol. 3, 58-67 (2001). | Article | PubMed |
18. Huttner, W.B. & Brand, M. Asymmetric division and polarity of neuroepithelial
cells. Curr. Opin. Neurobiol. 7, 29-39 (1997). | Article | PubMed |
19. Verdi, J.M. et al. Mammalian NUMB is an evolutionarily conserved signaling
adapter protein that specifies cell fate. Curr. Biol. 6, 1134-1145
(1996). | PubMed |
20. Zhong, W., Feder, J.N., Jiang, M.M., Jan, L.Y. & Jan, Y.N. Asymmetric
localization of a mammalian numb homolog during mouse cortical neurogenesis.
Neuron 17, 43-53 (1996). | PubMed |
21. Zhong, W. et al. Mouse numb is an essential gene involved in cortical
neurogenesis. Proc. Natl. Acad. Sci. USA 97, 6844-6849
(2000). | Article | PubMed |
22. Petersen, P.H., Zou, K., Hwang, J.K., Jan, Y.N. & Zhong, W. Progenitor cell
maintenance requires numb and numblike during mouse neurogenesis. Nature
419, 929-934 (2002). | Article | PubMed |
23. Wakamatsu, Y., Maynard, T.M., Jones, S.U. & Weston, J.A. NUMB localizes in
the basal cortex of mitotic avian neuroepithelial cells and modulates neuronal
differentiation by binding to NOTCH-1. Neuron 23, 71-81 (1999). | PubMed |
24. Verdi, J.M. et al. Distinct human NUMB isoforms regulate differentiation vs.
proliferation in the neuronal lineage. Proc. Natl. Acad. Sci. USA 96, 1047210476 (1999). | Article | PubMed |
25. Zilian, O. et al. Multiple roles of mouse Numb in tuning developmental cell
fates. Curr. Biol. 11, 494-501 (2001). | Article | PubMed |
26. Shen, Q., Zhong, W., Jan, Y.N. & Temple, S. Asymmetric Numb distribution is
critical for asymmetric cell division of mouse cerebral cortical stem cells and
neuroblasts. Development (in press).
27. Qian, X., Goderie, S.K., Shen, Q., Stern, J.H. & Temple, S. Intrinsic programs of
patterned cell lineages in isolated vertebrate CNS ventricular zone cells.
Development 125, 3143-3152 (1998). | PubMed |
28. Qian, X. et al. Timing of CNS cell generation: a programmed sequence of
neuron and glial cell production from isolated murine cortical stem cells. Neuron
28, 69-80 (2000). | PubMed |
29. Berdnik, D., Torok, T., Gonzalez-Gaitan, M. & Knoblich, J. The endocytic protein
alpha-Adaptin is required for Numb-mediated asymmetric cell division in
Drosophila. Dev. Cell 3, 221 (2002). | PubMed |
30. Santolini, E. et al. Numb is an endocytic protein. J. Cell Biol. 151, 1345-1352
(2000). | Article | PubMed |
31. Rice, D.S., Northcutt, G.M. & Kurschner, C. The Lnx family proteins function as
molecular scaffolds for Numb family proteins. Mol. Cell. Neurosci. 18, 525-540
(2001). | Article | PubMed |
32. Nie, J. et al. LNX functions as a RING type E3 ubiquitin ligase that targets the
cell fate determinant Numb for ubiquitin-dependent degradation. Embo J. 21,
93-102 (2002). | Article | PubMed |
33. Xie, Y. et al. Identification of a human LNX protein containing multiple PDZ
domains. Biochem. Genet. 39, 117-126 (2001). | Article | PubMed |
34. Susini, L. et al. Siah-1 binds and regulates the function of Numb. Proc. Natl.
Acad. Sci. USA 98, 15067-15072 (2001). | Article | PubMed |
35. Justice, N.J. & Jan, Y.N. Variations on the Notch pathway in neural
development. Curr. Opin. Neurobiol. 12, 64-70 (2002). | Article | PubMed |
36. Furukawa, T., Mukherjee, S., Bao, Z.Z., Morrow, E.M. & Cepko, C.L. rax, Hes1,
and notch1 promote the formation of Muller glia by postnatal retinal progenitor
cells. Neuron 26, 383-394 (2000). | PubMed |
37. Morrison, S.J. et al. Transient Notch activation initiates an irreversible switch
from neurogenesis to gliogenesis by neural crest stem cells. Cell 101, 499-510
(2000). | PubMed |
38. Wakamatsu, Y., Maynard, T.M. & Weston, J.A. Fate determination of neural
crest cells by NOTCH-mediated lateral inhibition and asymmetrical cell division
during gangliogenesis. Development 127, 2811-2821 (2000). | PubMed |
39. Johansson, C.B. et al. Identification of a neural stem cell in the adult
mammalian central nervous system. Cell 96, 25-34 (1999). | PubMed |
40. Seery, J.P. & Watt, F.M. Asymmetric stem-cell divisions define the architecture
of human oesophageal epithelium. Curr. Biol. 10, 1447-1450
(2000). | Article | PubMed |
41. Bellaiche, Y., Gho, M., Kaltschmidt, J.A., Brand, A.H. & Schweisguth, F. Frizzled
regulates localization of cell-fate determinants and mitotic spindle rotation
during asymmetric cell division. Nat. Cell Biol. 3, 50-57
(2001). | Article | PubMed |
ACKNOWLEDGEMENTS
M.C. was funded by a Long-Term Fellowship from the Human Frontier
Science Program Organization, and M.R. was funded by the Medical
Research Council (UK). We thank W. Zhong and Y. N. Jan for sharing
their results prior to publication, and members of the Raff Lab for
comments and support.
Figure 1: Role of Numb in Drosophila sensory organ
development.
(a) In wild-type flies, Numb is asymmetrically segregated to
the IIb daughter cell when the SOP divides. The IIb cell then
divides to produce a neuron and a sheath cell, whereas the
IIa cell divides to produce a socket cell and a hair cell. (b) In
Numb-deficient mutants, both daughter cells of the SOP
division become IIa cells. (c) When Numb is overexpressed
in the SOP, both daughter cells of the SOP division become
IIb cells.
Figure 2: Symmetric and asymmetric segregation of a
cell-fate determining protein that is localized to the
apical cortex in vertebrate neuroepithelial cells.
(a) In a cell division with a horizontal mitotic spindle
(oriented parallel to the plane of the neuroepithelium), the
cell fate protein is inherited by both daughter cells. (b) In a
cell division with a vertical mitotic spindle, it is inherited by
only one daughter cell.
Figure 3: m-Numb distribution in dividing mouse
cortical neuroepithelial cells.
(a) When m-Numb is distributed diffusely around the cell
cortex of a neuroepithelial cell, it is inherited at division by
both daughter cells, which both become neuronal. (b) When
m-Numb is localized to one pole of the neuroepithelial cell
and is asymmetrically segregated to only one of the two
daughter cells at division, the daughter that inherits mNumb tends to become neuronal; the other daughter tends
to remain a neuroepithelial cell. (c) In some divisions where
m-Numb is asymmetrically segregated to one daughter cell,
the two daughters both become neurons, but the neurons
appear to be different: the cell that inherits m-Numb
produces longer neurites.