Mother's Love

by Elio

Bi­nary fis­sion is a most im­pres­sive in­ven­tion. In one fell swoop, it en­sures that prog­eny cells are born alike and en­dowed with the same po­ten­tial for growth and sur­vival. Sim­ple as it sounds, it must have taken con­sid­er­able evo­lu­tion­ary con­tor­tions to make it func­tion so well through­out the liv­ing world. But there are cells that have adopted an al­ter­na­tive mech­a­nism, where cell di­vi­sion is asym­met­ri­cal, where one prog­eny cell is made from a "mother cell" that keeps gen­er­at­ing "ba­bies." The best known ex­am­ple is, of course, bud­ding in yeast. But other cells also arise in this fash­ion, in­clud­ing some bac­te­ria, the sex­ual spores of mush­rooms, and even some plant cells.

So, is there an ad­van­tage to by­pass­ing bi­nary fis­sion and bud­ding in­stead? It would seem that way. Re­cent work from Tom Nyström's lab has shown that pro­teins that be­come dam­aged in the course of cell growth flow back into the mother cell and leave the young bud free of such im­ped­i­ments. The dam­age to pro­teins is of­ten due to ox­i­da­tion by re­ac­tive oxy­gen species. Dam­aged pro­teins tend to form ag­gre­gates. This can be bad, get­ting rid of them is good. How do these pro­teins ac­cu­mu­late in the mother cell? In­ter­est­ingly, pro­tein ag­gre­gates hitch a ride on actin fil­a­ments that grow from the grow­ing bud to the mother cell. Such fil­a­ments are as­sem­bled at the tip of the bud in a struc­ture the au­thors call a "po­lar­i­some," which is made up of core pro­teins plus some in­volved in actin poly­mer­iza­tion (formins). Also re­quired is the age-re­tar­dant deacety­lase, a pro­tein called Sir2 and aka sir­tuin. Pre­vi­ously known as a life span modulator—not just in yeast but in worms, fish, and mam­mals as well—Sir2 has now been found to also be in­volved in actin-re­lated processes, hence in po­lar­i­some for­ma­tion. It gets more com­pli­cated. For an overview, we sug­gest a com­men­tary by Guar­ente.

The po­lar­i­some in a form­ing yeast bud. Actin ca­bles grow­ing out from the po­lar­i­some trans­port pro­tein ag­gre­gates to the mother cell. Source

Now let's look at this story in a broader con­text. It's not just about ship­ping dirty laun­dry off to mother. One con­se­quence of the asym­me­try of bud­ding is that the mother cell re­tains its bod­ily in­tegrity bud af­ter bud, whereas this is lost when a cell di­vides by bi­nary fis­sion. In yeast, a mother cell can bud some 15–30 times, af­ter which it conks out. How do we know? Count­ing the num­ber of times a cell gives off buds is done pa­tiently un­der the mi­cro­scope, us­ing a mi­cro­ma­nip­u­la­tor to re­move each daugh­ter cell once it sep­a­rates from the mother cell. Keep this up un­til the mother cell gives off no more buds. Imag­ine teas­ing the new cells away for the mother cell 30 times or so! (This seems to have been done first in 1950 by A. A. Bar­ton, work­ing for a British brew­ing com­pany.) This phe­nom­e­non is called senes­cence, and is vi­su­ally il­lus­trated by wrin­kles of old age and the un­usu­ally large size of the Grande Dame. Newly formed cells start the process anew, each daugh­ter cell be­com­ing a mother cell of its own. How­ever, in time, the newly made cells are less com­pe­tent for fur­ther bud­ding. Not sur­pris­ingly, yeast is a fa­vorite for stud­ies of cell po­lar­iza­tion and its pos­si­ble role in senes­cence. Many pa­pers have been writ­ten on this sub­ject.

A fa­vorite con­nec­tion be­tween yeast bud­ding and ag­ing re­lies on a 120-year-old the­ory by Au­gust Weis­mann. He pos­tu­lated that ag­ing evolved from the need to sep­a­rate germ cells from so­matic cells. Germ cells need to be pro­tected from dam­age; so­matic cells can "take it." One of the rea­sons given is that ad­di­tional re­sources must be be­stowed on germ cells to en­sure their ge­netic sta­bil­ity. So­matic cells, in con­trast, do not have such mech­a­nisms and thus ac­cu­mu­late dam­age.

This is one way to think about asym­met­ric cell di­vi­sion. For­mally speak­ing, the mother cell acts as a so­matic cell that pro­duces mul­ti­ple germ cells, the buds. Each, when grown, be­comes a mother cell with full re­pro­duc­tive po­ten­tial, able to pro­duce a full com­ple­ment of buds of her own. Dur­ing bud­ding, the young bud es­capes from the cell dam­age rep­re­sented by the ag­gre­gated pro­teins, thus foil­ing at least that as­pect of cell ag­ing.

A Ex­po­nen­tially grow­ing young yeast cells to com­pare their size and mor­phol­ogy to that of old cells. B A typ­i­cal lifes­pan de­ter­mi­na­tion. The num­ber of bud­ding cy­cles that each of a set of 50 'vir­gin' cells un­der­goes be­fore it stops di­vid­ing was de­ter­mined by micromani­pulation and count­ing of bud­ding cy­cles. C M is the ter­mi­nal mother cell af­ter 15 cell cy­cles. Note the enor­mous size as com­pared to young cells and the sur­face changes. D14 is the sec­ond but last daugh­ter that did not com­pletely sep­a­rate from the mother and did not give rise to new liv­ing cells. Source

If asym­met­ric cell di­vi­sion af­fords such pro­tec­tion of the germ line, why don't all cells do this? The ques­tion is not ter­ri­bly rel­e­vant to mul­ti­cel­lu­lar so­matic cells, given that they are not in­volved in germ line prop­a­ga­tion (un­less some in­ves­ti­ga­tor teases their nu­clei out and in­tro­duces them into eggs). But how come more uni­cel­lu­lar mi­crobes haven't adopted the bud­ding strat­egy? That is a ques­tion for an­other time.

Given that yeast is the best known of all eu­kary­otic or­gan­isms, al­low­ing end­less kinds of ge­netic ma­nip­u­la­tions, it's no won­der that it has be­come a model for the study of ag­ing. And here I thought that I would be a good sub­ject for re­search­ing what hap­pens in old age!

Ad­den­dum  As Qet­zal noted (see his com­ment be­low), I could have men­tioned that a pos­si­bly anal­o­gous phe­nom­e­non has been re­ported for bac­te­ria. When E. coli di­vides, the "old" cell pole ac­cu­mu­lates chap­er­ones in­volved in the ag­gre­ga­tion of (pre­sum­ably) dam­aged pro­teins. Even­tu­ally the "old" cells lose their re­pro­duc­tive ca­pa­bil­ity. Some­thing anal­o­gous takes place in Caulobac­ter cres­cen­tus. Thus, bac­te­ria may also use the strat­egy of seg­re­gat­ing dam­aged pro­teins in ag­ing cells, to the ad­van­tage of the pop­u­la­tion as a whole.

Ref­er­ence

Liu, B., Lars­son, L., Ca­ballero, A., Hao, X., Öling, D., Grantham, J., & Nys­tröm, T. (2010). The Po­lar­i­some Is Re­quired for Seg­re­ga­tion and Ret­ro­grade Trans­port of Pro­tein Ag­gre­gates Cell, 140 (2), 257–267 DOI: 10.1016/j.cell.2009.12.031