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Review
Molecular control of brain size: Regulators of neural stem celllife, death and beyond
Bertrand Josepha, Ola Hermansonb,⁎
aDepartment of Oncology-Pathology, Cancer Centrum Karolinska (CCK), Karolinska Institutet, Stockholm, SwedenbLinnaeus Center in Developmental Biology for RegenerativeMedicine (DBRM), Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
Received 11 March 2010Accepted 15 March 2010Available online 19 March 2010
The proper development of the brain and other organs depends on multiple parameters, includingstrictly controlled expansion of specific progenitor pools. The regulation of such expansion eventsincludes enzymatic activities that govern the correct number of specific cells to be generated via anorchestrated control of cell proliferation, cell cycle exit, differentiation, cell death etc. Certain proteinsin turn exert direct control of these enzymatic activities and thus progenitor pool expansion andorgansize. The members of the Cip/Kip family (p21Cip1/p27Kip1/p57Kip2) are well-known regulators ofcell cycle exit that interactwith and inhibit the activity of cyclin–CDKcomplexes,whereasmembers ofthe p53/p63/p73 family are traditionally associated with regulation of cell death. It has howeverbecomeclear that the roles for theseproteins are not as clear-cut as initially thought. In this review,we
discuss the roles for proteins of the Cip/Kip and p53/p63/p73 families in the regulation of cell cyclecontrol, differentiation, anddeath of neural stem cells.We suggest that these proteins act asmolecularinterfaces, or “pilots”, to assure the correct assembly of protein complexeswith enzymatic activities atthe right place at the right time, thereby regulating essential decisions in multiple cellular events.
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Introduction
Proper organ development is dependent on a wide variety ofparameters, including environmental inputs such as secretedsignaling factors, cell–cell contact mediators, extracellular matrix,oxygen levels, gravity, nutrition, as well as intrinsic cues such assignaling pathways, transcription factor expression, DNA occu-pancy, and chromatin structure. A crucial component in regulatingorgan size is the balanced regulation of proliferation and cell deaththat is required to achieve the correct number of specific cell typeswithin an organ and regions thereof. Whereas cells inmany organsretain the capacity to divide also in the adult, other systems, suchas the adult brain, consist to a large extent of non-dividing,postmitotic cells. Hence the delicate control of cell division, cellsurvival, cell cycle exit, and timing of differentiation duringdevelopment is of utter importance to achieve the appropriatenumber of specific cell types, and the final size of the brain.
Most dividing cells in the developing brain are not fullydifferentiated and, at least during early and mid-gestation, to alarge extent multi- or bi-potent. As they divide either symmetri-cally or asymmetrically, these progenitors will give rise to acontinuous supply of undifferentiated progenitors by self-renewal[1]. In combination with the differentiation capacity, theseprogenitors are therefore often referred to as neural stem cells(NSCs). The progenitors and NSCs mostly reside in the ventricularregions of the developing brain. In the forebrain, including thedeveloping cerebral cortex, these undifferentiated neural cells canbe divided into apical and basal progenitors, where apicalprogenitors constitute the neuroepithelium and display NSCcharacteristics, whereas the basal progenitors reside in thesubventricular zone and are often referred to as intermediateprogenitors [1]. While being undifferentiated, these two classes ofprogenitors can be distinguished by several criteria, includingdifferentiation potential and expression of markers such as specifictranscription factors. Different regions of the central nervoussystem display variations in the principles of assembly. Thedevelopment of the organization of the cerebral cortex is basedon an “inside-out” manner where later-born neural progenitorsmigrate from the ventricular and subventricular zones past theearlier-born and thus settle in more superficial layers. In addition,interneurons (inhibitory) and populations of oligodendrocyteprecursors migrate in a tangential manner from the ventraltelencephalon to contribute to the cortical structures.
The right enzyme at the right place and the right time
In addition to the regulatory mechanisms underlying migration,axon pathfinding, and other fundamental principles underlyingthe rise of the exquisite architecture of the brain [2], proper celldivision during brain development is depending on numerousprecisely orchestrated events aiming at executing and coordinat-ing spatially and temporally controlled enzymatic activitiesgoverning accurate DNA replication and chromatin modificationsthat should be inherited or erased to allow proper permission ofgene activation and higher order chromatin structure. Control ofmultiple levels of micro- and nano-architectural subcellularorganization is thus required to achieve the correct cellularphenotype. The correct guidance of enzymes, executed by
transcriptional regulators, scaffold proteins, and nucleosomeorganization, in combination with the regulation of the activityof those enzymes that regulate acetylation, methylation, phos-phorylation, ubiquitination, and additional modifications of thechromatin polymer and other structural components, is thuscritical for multicellular existence.
In transcription, the cellular levels of certain enzymes influ-encing transcriptional activity, such as histone deacetylases andacetyl transferases, vary in a cell-specific fashion and displayspecific expression patterns during brain development andthereby provide cell-specific enzymatic activity [3]. Still, many ofthese factors have been shown to play redundant roles in essentialdevelopmental events. Added to lessons from cancer biology, itseems that the regulation of the cellular levels of a certain enzymealone may not provide a secure enough mechanism for thedeveloping cell to depend on for proper differentiation anddevelopment. Notably, the regulation of subcellular localizationas well as cell type specific promoter occupancy of these enzymesand complexes provides an additional and plausibly essential layerof gene expression control [4].
Transcription factors, without enzymatic activity of themselves,bind to specific sequences of DNA, and interact and thus recruitcomplexes of proteins with proper enzymatic activity to controlchromatin structure and integrity, further recruitment, assembly,or maintenance of regulator complexes, and/or recruitment orinhibition of recruitment of RNA polymerase II [5]. Transcriptionfactors are thus to be regarded as scaffold proteins, andmany of theother proteins in complexes regulating transcription are also non-enzymatic. In repression of transcription, examples of such non-enzymatic complex proteins are NCoR, SMRT, Sin3a and Groucho/TLE proteins [5]. Also smaller but powerful proteins, such as theLIM-only (LMO) proteins function as scaffold factors, and enzy-matic proteins such as histone deacetylases are known to also exertnon-enzymatic dependent function in transcription. It is conceiv-able that such extra-enzymatic functions are to provide the correctinterfaces for proper complex assembly.
Hence, the levels and location of these “molecular pilots”thereby become absolutely critical for the correct assembly ofcomplexes and guidance of the proper enzymatic activity to theright place at the right time.
Molecular pilots of cell cycle regulation
Cell proliferation, survival and death are likewise events dependingon sequential activities by specific enzymes that are, at least in part,regulated by levels and subcellular localization of non-enzymaticassembly factors. Cell division is dependent on “checkpoint”-regulating cyclin-dependent kinases (CDKs), and the activities ofthese CDKs can be regulated by various mechanisms. Thesemechanisms include the regulation by non-enzymatic proteins thatinteract directly with cyclin–CDK complexes and inhibiting theiractivity. CDK inhibitors (CKI) include the so-called Ink4 family andthe Cip/Kip family [6]. The Cip/Kip family of cell cycle inhibitorsconsists of three factors in mammals, p21Cip1, p27Kip1, andp57Kip2, and in this short review the roles for these proteins in theregulation of NSC proliferation and differentiation will be discussed.
The CKIs are functionally related to another family of non-enzymatic factors well known for their involvement in regulatingcell death, namely the p53/p63/p73 family. These proteins are
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functioning both upstream and downstream of the CKIs, and thisreview will provide an overview of the roles for these factors, withfocus on p63 and p73, in NSC life, death, and differentiation.
p27Kip1 — sometimes less yields more
p27Kip1mediates arrest in the G1 phase by binding to and preventthe activity of cyclin E–CDK2 and cyclin D–CDK4 complexes [6].Mice lacking p27Kip1 display increased size in many organs,including the brain, thus emphasizing the role for p27Kip1 in cellcycle exit control [7] (and references therein). In line with this,there are numerous reports investigating various roles for p27Kip1in neural tumorigenesis. Studies in primate brains have suggestedan even more specific role in cortical development as theexpression of p27Kip1 during development is especially high inspecific areas of the cortex (e.g., area 18) [8]. This observationpoints to the intriguing possibility that p27Kip1 could play a role inregionalization and in the regulation of the expansion of specificprogenitor pools. In addition, p27Kip1 has been elegantlyimplicated in the regulation of the timing of oligodendrocyteprecursor cell cycle exit and terminal differentiation, as the levelsof p27Kip1 increase in the progression of differentiation [9].
Several studies using various approaches have reported thatp27Kip1 plays an essential role in migratory events in the dorsalpallium [10,11]. During recent years, a number of studies havereported that p27Kip1 also plays roles in neuronal differentiation,and at least a subset of these functions can be dissociated from itsrole in cell cycle regulation [2]. Mice exhibiting either gene deletionor overexpression of p27Kip1 show layer-specific changes inneuronal differentiation in the cerebral cortex [7,12]. However,playing with the length of the G1 phase should influence theneuronal differentiation [6], and the mechanisms underlying theseeffects of changes in the levels of p27Kip1 remained unclear.However, subsequent to the initial reports from muscle differenti-ation showing that p57Kip2 could interact with the myogenic bHLHtranscription factorMyoDand influence its activity by inhibit proteindegradation, it was demonstrated that p27Kip1 interacts with andstabilizes the neurogenic bHLH transcription factor Neurogenin2(Ngn2), both factors primarily expressed in the dorsal palliumof thedeveloping telencephalon [11]. Rescue experiments and comple-mentary in vitrowork in slices and cell cultures further demonstrat-ed that the effect of p27Kip1 on neuronal differentiation could beuncoupled from that of cell cycle regulation as well as migration. Akey to the separate functions of p27Kip1 can be found in that specificdomains of the protein interact with different sets of proteinsthereby influencing distinct cellular events. In the N-terminal half ofp27Kip1 there is a specific motif that is required for the interactionwith cyclin–CDK complexes that is dispensable for the interactionwith Ngn2. In parallel, it is the C-terminal half of p27Kip1 that isrequired for the effects on migration, possibly by interfering withRho–ROCK signaling [11]. Hence, the levels and subcellular locali-zation of p27Kip1 will determine which proteins that the specificdomains will interact with, and thereby functional specificity isachieved. It is thereforenot surprising that recent studies onp27Kip1function in neural stem cells have focused on increasing theunderstanding of the regulation of the levels and subcellularlocalization of the protein. Future studies may also aim atunderstanding the transcriptional effects elicited by the interactionbetween p27Kip1 and Ngn2 at an enzymatic level.
p57Kip2 — location, location, location
The role for p57Kip2 in brain development is less clear, in spite ofthe fact that p57Kip2 is the only CKI of the Cip/Kip family that isabsolutely required for survival [13]. p57Kip2 share manybiochemical and cellular functions with p27Kip1, at least in vitro,but in contrast to mice harboring gene deletion of p27Kip1 thatshow increased size of the body and several organs, and alsoincreased tumor development, p57Kip2 knock-out mice rathershow increased apoptosis and less proliferation in multiple organs[13]. This phenotype initiated discussions whether p57Kip2actually acted as a CDK inhibitor at all in vivo. However, elegantgenetic models where the p57Kip2 gene was replaced by p27Kip1,and thus under the regulation of the promoter of the p57Kip2 gene,demonstrated that many of the essential functions of p57Kip2 canbe carried out by p27Kip1 [14]. This result emphasizes theimportance of the developmental expression pattern of thedifferent members of the Cip/Kip family, and p57Kip2 indeeddisplays dynamic changes in spatial expression during embryonicdevelopment.
In the CNS, p57Kip2 has recently been shown to control neuralprecursor proliferation at several axis of the developing nervoussystem. p57Kip2 has also been shown to play a direct role inregulating the activity of transcription factors implicated inneuronal differentiation. For example, p57Kip2 interacts directlywith the nuclear receptor Nurr1 and promote maturation ofdopaminergic neurons in postmitotic precursors [15]. However,during development, p57Kip2 are also expressed in mitoticmultipotent neural progenitors in the ventricular and subventri-cular zones of specific regions of the forebrain, including theventral telencephalon [16]. As mentioned above, ventral telen-cephalon is a major source for cortical interneurons and oligoden-drocytes. Indeed, by gain and loss of function studies in NSCs invitro it was demonstrated that p57Kip2 exerts an inhibitoryfunction on neuronal differentiation that can be uncoupled fromits effects on proliferation and cyclin–CDK complex interaction[16]. This can be attributed, at least in part, to an interaction withthe neurogenic bHLH transcription factor Mash1, as p57Kip2 wasfound to bind to Mash1 and repress its activity in transcriptionalassays. Chromatin immunoprecipitation assays further indicatedthat p57Kip2 was enriched at Mash1-binding sites on the Dlx1/2gene, which provides a model for the inhibitory effects of p57Kip2on neuronal differentiation [16]. The histone acetyl transferasesCBP and p300 has been shown to be required for proper neuronaldifferentiation in telencephalic contexts [3], and future studies mayelucidate whether p57Kip2 binding to Mash1 may interfere with therecruitment of these enzymes to essential genes.
In addition to interneurons, ventral telencephalon is known togive rise to early waves of oligodendrocytes. Due to the expressionof p57Kip2 in a subset of progenitors in the ventral telencephalonand a hypothetical repression of Dlx1/2 – which in turn has beenshown to inhibit oligodendrogenesis – it is tempting to speculatewhether a potential role for p57Kip2 could be to repress neuronaldifferentiation to secure proper oligodendrocyte proliferation,specification and/or differentiation. Proper levels of p57Kip2 arenamely critical for correct proliferation as well as differentiation ofprimary oligodendrocyte progenitor cells [17]. Furthermore, thetiming and levels of Mash1 and Dlx1/2 expression, as well asNotch signaling, have been shown to be critical parameters to
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secure the proper proliferation, differentiation and migration ofventral telencephalic progenitors [18]. The strong link of p57Kip2,as well as p27Kip1, to Notch signaling suggest a potential role infate choice and lineage decision, and it will be of interest toinvestigate whether more subtle changes in p57Kip2 cellularlevels, as well as subcellular localization, can bias distinctprogenitor pools to acquire specific cell fates.
p21Cip1 — still in the shadows
p21Cip1 may be the most intensely studied factor of the Cip/Kipfamily, as it is prominently down-regulated in various tumor celltypes and in addition been shown to be regulated by histonedeacetylase (HDAC) activity and thus a target for HDAC inhibitors,such as valproic acid, SAHA, and trichostatin A. Much less isunderstood regarding the role for p21Cip1 in embryonic NSCcharacteristics. In one of few published studies aiming directly atinvestigating the role for p21Cip1 in neural stem cells, Kippin et al.demonstrated that loss of p21Cip1 results initially in a highernumber of adult neural progenitors followed by a subsequentdepletion of the neural stem cell pool, thereby pointing to thatp21Cip1 is required for the maintenance of neural stem cell self-renewal [19]. Indeed, p21Cip1 has been found to be a target formany factors essential for neural progenitor expansion, and thusthe phenotypes resulting from genetic manipulation of suchfactors have been attributed to aberrantly increased or decreasedexpression of p21Cip1. For example, it has been shown that FoxG1represses p21Cip1 expression during telencephalic developmentto allow cortical expansion [20], and mice harboring gene deletionof HDAC1 show severe neuroepithelial defects in early develop-ment that could be associatedwith increased levels of p27Kip1 andp21Cip1 [21]. Interestingly, loss of p53 in adult NSCs is associatedwith poor self-renewal and a down-regulation of p21Cip1 [22](see further below). As the interest for mechanisms underlyingprogenitor pool expansion as well as NSC renewal and senescenceincreases, more systematic in vivo investigations regarding therole/s for p21/Cip1 in brain development are likely to follow.
p53 — gatekeeper of neural stem cell self-renewal
When discovered in 1979, p53 was, due to its physical interactionswith viral proteins, thought to be an oncogene. However, in 1989its character as a tumor suppressor gene was finally revealed. p53knock-out mice show a high rate of spontaneous tumors [23], andwere at first seemed to have no apparent developmentalphenotype. However, later it was discovered that a large numberof embryos die in utero as a result of midbrain exencephaly, aneural tube malformation, probably due to a deficit in progenitorcell apoptosis [24]. In fact during embryonic neural development,when either cell cycle regulation or DNA integrity are perturbed,p53 becomes the major proapoptotic protein in NSCs [25], anddepletion of p53 is sufficient to rescue neural precursors fromapoptosis seen in mice lacking pRb, DNA Ligase IV or XRCC4[25,26] (and references therein). In addition, p53 is able after DNAdamage to promote the differentiation of mouse embryonic stemcells into other cell types that undergo efficient p53-dependentcell cycle arrest and apoptosis. p53 binds to the promoter of Nanog,a gene required for embryonic stem cell self-renewal, suppresses
Nanog expression, and thereby enhance embryonic stem celldifferentiation [27]. p53 is also expressed in the neural stem celllineage in the adult brain, where it negatively regulates prolifer-ation and survival, and thereby self-renewal, of adult neural stemcells [22]. Thus, p53 is a key regulator of genetic stability and can beconsidered as a gatekeeper of self-renewal in NSCs, functioning as aproapoptotic protein or differentiation factor in neural precursors.
p63 and p73 as neural progenitor stemness rheostats
At first, it was hard to explain why only a fraction of the p53-deficient mice displayed a developmental phenotype. However,after the discovery of the p53-family members p63 and p73 in thelate nineties, [28,29], the partial phenotype could somewhat beexplained by the two new family members playing a compensa-tory role in a p53-null background [30]. Over the years, numerousreports have demonstrated the p53 family of transcription factorsto be key regulators of survival and apoptosis in the developing,adult and injured nervous system (Fig. 1). Like p53, severaldifferent protein isoforms of p63 and p73 have been reported,whose functions may compete with, synergize with, or beunrelated to those of p53 [31–33]. The isoforms come in twomajor flavors, generated by differential promoter usage: thosecontaining a potent amino-terminal transactivation domain – theTA isoforms – and those lacking that region – the so-called ΔNisoforms – that function, at least in part, as naturally occurringdominant-inhibitory p53 family members. Adding to this com-plexity, alternative splicing gives rise to isoforms with differentcarboxy-terminals [31,33].
p63 plays a key function in development as it is essential for thesurvival of epithelial stem cells. Here, the truncated ΔN isoform ispredominant and critical for the maintenance of progenitor cellsnecessary for a sustained epithelial development and morpho-genesis [29,34,35]. Consequently, p63-deficient mice are distin-guished by a loss of stem cells in the affected tissues [36], and micemostly suffer from a failure in the development stratifiedsquamous epithelia and their derivates [35,37]. In addition,TAp63 plays an essential proapoptotic function during the CNSdevelopment [38]. Sympathetic neurons express TAp63 during thedevelopmental death period, and TAp63 levels increase followingNGF withdrawal. Overexpression of TAp63 causes neuronalapoptosis in the presence of NGF, while cultured p63−/− neuronsare resistant to apoptosis following NGF withdrawal. TAp63 is alsoessential in vivo, since embryonic p63 null mice display a deficit innaturally occurring sympathetic neuron death. Interestingly,whereas both TAp63 and p53 induce similar apoptotic signalingproteins, TAp63 induces neuronal death in the absence of p53, butp53 requires concurrent p63 expression for its proapoptoticactions. Both TAp63 and DNp63 are expressed in corticalprecursors, cortical neurons and in vivo in the cortex of embryonic,postnatal, and adult brains [38]. The genetic knockdown of p63causes apoptosis of cortical precursors and cortical neurons, whichcan be rescued by expression of ΔNp63, but not TAp63 isoforms.This cortical precursor cell death appears to be the consequence ofp53 activation, since apoptosis induced by loss of p63 can berescued by simultaneous silencing of p53 [25]. Thus, while TAp63is essential for developmental sympathetic neuron death – likelyfunctioning both on its own and as an obligate proapoptoticpartner for p53 – DNp63 is essential for the survival of embryonic
Fig. 1 – Amodel of the p53/p63/p73 family as neural stem cell rheostats. In addition to the well-known association of these factorsin regulation of cell death, the levels of these proteins and various variants of p63 and p73 influences neural stem cell self-renewaland cell division as well as differentiation into terminal cell fates and lineage decision. It is conceivable that the multiple roles forthese proteins in neural stem cell state and fate can be attributed to interactions with distinct protein complexes.
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cortical precursors and newly born cortical neurons, a role that itplays by antagonizing the proapoptotic actions of p53 (Fig. 1).
Previous analyses of p73 deficientmice have demonstrated thatp73 is critical for the development andmaintenance of the nervoussystem [39]. Indeed, p73 null mice exhibit hippocampal dysgenesiswith a gradual but persistent postnatal loss of neuronswith greatlyenlarged ventricles (hydrocephalus) and greatly reduced corticaltissue [39,40]. Expression of p73 is enriched in the nervous system[39]. In sympathetic neurons within the developing brain, p73 ispredominantly expressed as the amino-terminal truncated (ΔN)isoform [41] and it has been suggested that ΔNp73 might mediatesurvival and migration of neurons, an action essential for theconstant remodeling of the hippocampus all throughout life. Incontrast, the full-length TAp73 isoformhas recently been shown, inTA-isoform specific deficientmice, to be critical not for cell survival,but for appropriate genesis of the hippocampus [42].
Of note, TAp73 expression induces oligodendrocyte precursorcell differentiation, a process inhibited by ΔNp73 [43]. Thepreventive effect of ΔNp73 on apoptosis is not only limited todevelopingneurons, but also seems tobe required as a survival factorin adult neurons in response to stresses likeDNAdamageand trauma[40]. That is probably why abnormalities in ΔNp73 expression maypredispose toanaccelerated loss of neurons, as inneurodegenerativedisorders [30]. However, DNp73 is predominantly expressed inpostmitotic neurons in the embryonic brain [39], indicating that itlikely does not play a role in neural precursors, a conclusionsupported by the observation that DNp73 does not regulate survivalof cortical precursor cells [25]. Instead, as mentioned above, theamino-terminal truncated isoform of p63 appear to be the relevantprosurvival familymember for CNS neural precursors. However, it isnot only DNp63 that has an integral role in stem cell maintenancebut TAp73 also functions in the renewal of neural stem cells. Indeed,in TAp73−/− mice, the hippocampal precursors that are respon-sible for ongoing neurogenesis are significantly depleted, andneurogenesis is greatly decreased resulting in the hippocampal
dysgenesis. Genetic knockdown of TAp73 in embryonic corticalprecursors led to decreased precursor proliferation and increasedneuronal differentiation. This decreased self-renewal ultimatelyresulted in a reduced pool of neural stem cell. In summary, whereasΔNp73 functions as a major neuronal survival and maintenanceprotein, a function it fulfills at least partially by antagonizing full-length isoforms of p53 and p63 (Fig. 1); TAp73 is required for theself-renewal of neural stem cells. In conclusion, the p53 family playsa key role in determining the life versus death of both neurons andneural precursors in the CNS during development and adulthood.
Conclusions
The view of the Cip/Kip and p53/p63/p73 as simple regulators ofcell cycle and death, respectively, has changed and it is more likelythat these proteins rather act as molecular interfaces, or “pilots”, toassure the correct assembly of protein complexes with enzymaticactivities at the right place at the right time, thereby playingmultiple roles in essential biochemical and cellular events.Advanced genetic models and refined biochemical assays shouldprovide deeper insights into the delicate roles of these factors inthe fine-tuned regulation of neural stem cell characteristics,progenitor pool expansion, and ultimately brain size.
Acknowledgments
The authors would like to thank their lab members, friends at KI,and all those colleagues who encouraged and inspired this essay.OH and BJ are supported by grants from the Swedish ChildhoodCancer Foundation (BCF), the Swedish Foundation for StrategicResearch (SSF), the K&A Wallenberg Foundation, the KarolinskaInstitutet Foundations (KI Cancer), the Swedish Research Council,and the Swedish Cancer Society (CF).
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