Dispatch

Stem = Cell=20 Self-Renewal: Centrosomes on the Move

Clemens Cabernard and Chris Q. Doe =

Institutes of Neuroscience and = Molecular=20 Biology, HHMI, University of Oregon, Eugene, Oregon 97403, USA

Summary

Three = recent=20 studies show that centrosome asymmetry correlates with self-renewal of=20 Drosophila neural and germline stem cells and that equalizing = centrosomes=20 disrupts asymmetric cell division.

Stem cells need to balance self-renewal with = differentiation to maintain tissue homeostasis. One mechanism to ensure = stem=20 cell self-renewal is asymmetric cell division, in which one sibling = self-renews=20 while the other sibling initiates differentiation. It is thus important = to=20 identify stem cell polarity cues that direct the daughter cells to = self-renew or=20 differentiate. Now three recent papers show that centrosome asymmetry = correlates=20 with =E2=80=94 and is required for =E2=80=94 proper asymmetric cell = division in two model stem=20 cell systems, Drosophila larval neuroblasts and Drosophila = male=20 germline stem cells [1, 2, 3].

Previous work from the Fuller lab and others = has shown=20 that male germline stem cells undergo asymmetric cell division: one = daughter=20 cell remains connected by adherens junctions to somatic =E2=80=98hub = cells=E2=80=99 and=20 self-renews as a germline stem cell, and the other loses contact with = the hub=20 and begins to differentiate (the gonialblast) [4]. A new study = by=20 Yamashita et al.[1] provides = evidence that=20 centrosome asymmetry contributes to spindle orientation in the germline = stem=20 cell, and hence to reliable self-renewal of these stem cells. Using an = elegant=20 pulse=E2=80=93chase method to follow centriole segregation using a = GFP-tagged version of=20 the centriole protein PACT, they found that the oldest centrioles were = always=20 maintained in the germline stem cell. Conversely, newly formed = centrioles were=20 segregated into the differentiating gonialblast at every division (Figure 1,=20 left).

Figure 1. Asymmetric centrosome composition and = behavior affects stem cell renewal.

(Left) In Drosophila = male=20 germline stem cells (GLSC; light green), the mother centrioles (black = bars)=20 remain close to the hub cells (yellow), have more pericentriolar = material (PCM;=20 large circle), nucleate microtubules (lines), and are retained by the = stem cell;=20 the daughter centrioles (white bars) have less PCM (smaller circle), = fewer=20 microtubules, and are partitioned into the differentiating gonialblast = (GB;=20 red). (Right) In Drosophila larval=20 neuroblasts (NB, light green), one centriole pair/centrosome maintains = the PCM=20 and remains static near the apical cortex (defined by a cortical = crescent of=20 Pins localization; dark green). The other centriole pair is highly = mobile during=20 prophase (arrows), shows delayed recruitment of PCM material, and is = partitioned=20 into the differentiating ganglion mother cell (GMC; red). Mother and = daughter=20 centrioles (gray bars) have not yet been distinguished in this cell=20 type.

View larger version: [In=20 this window] [In new window]

So why does the mother centriole pair but = not the=20 daughter centriole pair remain in the stem cell, i.e. what are the = differences=20 between mother and daughter centrosomes? During prophase, the older = centrioles=20 accumulate more pericentriolar material (PCM) and maintain a more robust = microtubule array compared with the newly formed centrioles, and this = may help=20 anchor the older centrosomes to the germline stem cell cortex (and = possibly the=20 adherens junctions at the hub cell contact). If this model is correct, = then=20 reducing centrosomal microtubules should release the older centrosome = from the=20 site of contact between the germline stem cell and the hub. Indeed, = mutations in=20 centrosomin (which encodes a PCM protein required for efficient=20 microtubule nucleation) randomized the distribution of mother or = daughter=20 centrosomes relative to the hub=E2=80=93germline stem cell axis. = Interestingly,=20 Yamashita et al.[4] previously = observed=20 that centrosomin mutants show a 20=E2=80=9330% increase in = germline stem cells,=20 perhaps due to altered centrosome asymmetry or spindle orientation. In = the=20 future, it will be vital to test the precise role of centrosome = asymmetry in the=20 establishment of germline stem cell or gonialblast cell fate.

How does this finding relate to other stem = cells?=20 Satisfyingly, two other recent papers report centrosome asymmetry in=20 Drosophila larval neural stem cells, called neuroblasts [2, 3]. Larval = neuroblasts=20 divide asymmetrically to generate a larger self-renewing apical = neuroblast and a=20 smaller basal ganglion mother cell (GMC), which is committed to neural=20 differentiation. Now Rebollo et al.[2] and Rusan=20 et al.[3] show that = one=20 neuroblast centrosome remains associated with the neuroblast cortex = throughout=20 the cell cycle; this =E2=80=98apical=E2=80=99 centrosome maintains its = PCM and microtubule=20 nucleation potential. In contrast, during prophase the other centriole = pair=20 moves dynamically around the neuroblast cytoplasm without recruiting PCM = or=20 nucleating stable microtubules. At metaphase, this centriole pair ceases = motion,=20 accumulates the PCM components =CE=B3-tubulin and Polo kinase, nucleates = spindle=20 microtubules, and is segregated into the basal GMC [2, 3] (Figure 1, = right).=20 Although Rebollo et al.[2] used = individual=20 neuroblasts cultured in vitro, whereas Rusan et al.[3] used whole = brain=20 explant cultures, both studies reached essentially the same=20 conclusion.

How is centrosome asymmetry achieved in = larval=20 neuroblasts? It is easy to imagine that the mother centrioles are = maintained in=20 the static, PCM-rich apical neuroblast centrosome and the newly formed = daughter=20 centrosomes are partitioned into the ganglion mother cell, similar to = male=20 germline stem cell division, but this mechanism remains to be tested. = Rebollo=20 et al.[2] test a = different=20 hypothesis =E2=80=94 that neuroblast cortical polarity regulates = centrosomal asymmetry.=20 The Pins protein is normally localized to the neuroblast cortex = overlying the=20 static apical centrosome; Pins is thought to anchor this centrosome via = Mud, a=20 centrosomal and cortical Drosophila NuMA homolog [5, 6, 7]. Rebollo=20 et al.[2] find that in = pins mutants initial centrosome asymmetry is properly = established: one=20 centrosome is anchored at the neuroblast cortex whereas the second = centriole=20 pair migrates away. Subsequently, the apical centrosome begins to wander = through=20 the cytoplasm, similar to the basal centrosome. This suggests that Pins=20 contributes to the differences in apical and basal centrosome = behavior or=20 to linkage of apical microtubules to the cortex; it is unlikely = that=20 Pins is required to establish structural asymmetry between=20 centrosomes.

What is the function of centrosome asymmetry = in=20 neuroblasts? Rusan et al.[3] studied = asterless=20 (asl) mutants, which lack functional centrosomes [8]. = Surprisingly,=20 asl mutant neuroblasts frequently divide with normal spindle = orientation=20 (one spindle pole centered on the site of contact between the neuroblast = and the=20 ganglion mother cell), although a low frequency of symmetric divisions = are=20 observed [3]. Similar = results were=20 previously observed for centrosomin mutants [9]. These = results suggest=20 that centrosomes are required for reliable spindle orientation, but that = a=20 mechanism independent of centrosomes or astral microtubules also = contributes to=20 spindle orientation. The function of centrosome asymmetry remains to be = tested.=20 Rebollo et al.[2] show that = neuroblast=20 polarity (i.e. Pins function) maintains centrosome asymmetry; perhaps = there is a=20 feedback loop in which centrosome asymmetry contributes to neuroblast = polarity.=20 This would be consistent with a recent finding that only one spindle = pole is=20 able to induce Pins cortical polarity in embryonic neuroblasts [10].

In conclusion, these three papers provide=20 complementary data on the role of centrosome asymmetry in stem cell = division. In=20 both male germline stem cells and neuroblasts, the static PCM-rich = centrosome is=20 segregated into the stem cell, and perturbation of centrosome asymmetry = disrupts=20 reliable asymmetric cell division. It would be interesting to know = whether=20 the young centriole zooms around the germline stem cell similar to its = behavior=20 in neuroblasts; likewise it would be good to know if maternal centrioles = are=20 exclusively segregated into self-renewing neuroblasts as they are in = germline=20 stem cells. These answers should come soon. It will be more important to = address=20 the mechanisms establishing centrosome asymmetry and the function of = centrosome=20 asymmetry in stem cell self-renewal. For example, does the older = centrosome act=20 solely to ensure reliable spindle alignment along the cell polarity = axis? Or=20 might old and young centrioles/centrosomes contribute distinct factors = to each=20 sibling cell, helping to maintain one as a stem cell and push the other = towards=20 differentiation? The foundation has been laid for exploring the role of=20 centrosome asymmetry in fly neural and germline stem cells =E2=80=94 can = other stem=20 cells be far behind?

References

Summary
References

[1]=20 Yamashita, Y.M.,=20 Mahowald, A.P., Perlin, J.R., and Fuller, M.T. (2007). Asymmetric inheritance of mother = versus daughter=20 centrosome in stem cell division. Science = 315, 518-521. [Medline]=20

[2]=20 Rebollo, E.,=20 Sampaio, P., Januschke, J., Llamazares, S., Varmark, H., and Gonzalez, = C.=20 (2007). Functionally unequal centrosomes = drive spindle=20 orientation in asymmetrically dividing Drosophila neural stem=20 cells. Dev. Cell 12, = 467-474.=20 [Medline]=20 [Summary]=20 [Full=20 Text]

[3]=20 Rusan, = N.M., and=20 Peifer, M. (2007). A role for a novel = centrosome cycle in asymmetric cell division. J. Cell = Biol. 177, 13-20. [Medline]=20

[4]=20 Yamashita, Y.M.,=20 Jones, D.L., and Fuller, M.T. (2003). Orientation of asymmetric stem cell division by = the APC=20 tumor suppressor and centrosome. Science 301, = 1547-1550.=20 [Medline]=20

[5]=20 Siller, = K.H.,=20 Cabernard, C., and Doe, C.Q. (2006). The=20 NuMA-related Mud protein binds Pins and regulates spindle orientation in = Drosophila neuroblasts. Nat. Cell Biol. 8,=20 594-600. [Medline]=20

[6]=20 Bowman, = S.K.,=20 Neumuller, R.A., Novatchkova, M., Du, Q., and Knoblich, J.A. = (2006).=20 The Drosophila NuMA homolog Mud regulates = spindle=20 orientation in asymmetric cell division. Dev. Cell 10, = 731-742.=20 [Medline]=20 [Summary]=20 [Full=20 Text]

[7]=20 Izumi, = Y., Ohta,=20 N., Hisata, K., Raabe, T., and Matsuzaki, F. (2006). Drosophila Pins-binding protein Mud regulates=20 spindle-polarity coupling and centrosome organization. Nat. Cell = Biol. 8, 586-593. [Medline]=20

[8]=20 Giansanti, M.G.,=20 Gatti, M., and Bonaccorsi, S. (2001). The role=20 of centrosomes and astral microtubules during asymmetric division of = Drosophila=20 neuroblasts. Development 128,=20 1137-1145. [Medline]=20

[9]=20 Megraw, = T.L., Kao,=20 L.-R., and Kaufman, T.C. (2001). Zygotic=20 development without functional mitotic centrosomes. Curr. = Biol. 11, 116-120. [Medline]=20 [Summary]=20 [Full=20 Text]

[10]=20 Siegrist, S.E., and=20 Doe, C.Q. (2005). Microtubule-induced = Pins/Galphai cortical polarity in Drosophila = neuroblasts. Cell 123, 1323-1335. [Medline]=20 [Summary]=20 [Full=20 Text]

Functionally=20 Unequal Centrosomes Drive Spindle Ori...
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The=20 Drosophila NuMA Homolog Mud Regulates Spindle ...

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