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Engineering of Adult and

Benedikt Berninger1 and Sebastian Jessberger2

1Adult Neurogenesis and Cellular Reprogramming, Institute of Physiological Chemistry & Focus Program Translational , University Medical Center, Johannes Gutenberg University Mainz, 55128 Mainz, Germany 2Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland Correspondence: [email protected]; [email protected]

Neural stem/progenitor cells (NSPCs) retain their ability to generate newborn throughout life in the mammalian . Here, we describe how recently developed virus- and transgenesis-based techniques will help us (1) to understand the functional effects of neurogenesis in health and disease, (2) to design novel approaches to harness the potential for NSPC-associated endogenous repair, and (3) to induce the generation of neurons outside the main neurogenic niches in the adult brain.

he fact that neural stem/progenitor cells activity in vivo and/or subsequent neuronal T(NSPCs) persist in the adult brain, chal- integration in the adult brain. Furthermore, lenged previously held concepts of brain func- our understanding of the mechanisms regulat- tion in health and disease and opened novel ing neural differentiation has substantially im- possibilities to treat neurological disease by proved over the last years making it now possible harnessing the NSPC-associated potential for to redirect the fate of NSPC-derived, newborn brain repair (Gage 2000; Alvarez-Buylla and cells in the adult brain (Hack et al. 2005; Jess- Lim 2004; Gage and Temple 2013). However, berger et al. 2008; Brill et al. 2009). Besides these over the last decade, it has become clear that novel tools that target NSPCs in their endoge- targeting NSPCs for repair requires the detailed nous niches, basic understanding of the under- understanding of the biology of NSPCs and the lying neuronal differentiation of NSPCs in the underlying cellular and molecular mechanisms adult brain enabled novel approaches to induce that govern the distinct steps of neural develop- the generation of neurons also in nonneurogen- ment from dividing NSPCs to integrating neu- ic regions throughout the adult brain (Jessber- rons (Ming and Song 2011). Based on findings ger and Gage 2009; Amamoto and Arlotta 2014; obtained by aiming to understand the basic Heinrich et al. 2015). In addition, novel cellular mechanisms of , a number sources such as NSPCs derived from induced of technical advancements have substantially pluripotent stem cells (iPSCs), will enable us to increased our toolbox to manipulate NSPC study mechanisms of NSPC activity and neuro-

Editors: Fred H. Gage, Gerd Kempermann, and Hongjun Song Additional Perspectives on Neurogenesis available at www.cshperspectives.org Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a018861 Cite this article as Cold Spring Harb Perspect Biol 2016;8:a018861

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B. Berninger and S. Jessberger

nal differentiation in healthy and diseased hu- Snyder et al. 2005; Saxe et al. 2006). However, man tissue and may also represent a novel source given that the whole organism depends on prop- for exogenous cell-replacement strategies (Yu er levels of cell proliferation and the fact that et al. 2013, 2014). irradiation also injures postmitotic cells, these approaches are likely to be associated with un- wanted side effects that are bound to complicate MANIPULATING LEVELS OF ADULT the interpretation of behavioral tests (Fig. 1). NEUROGENESIS Thus, the focus over the years has been to de- Over the last decade, a plethora of approaches velop genetic or virus-based strategies to manip- have been developed to reduce or to enhance ulate levels of neurogenesis. The most common levels of adult neurogenesis with the aim to principle used is to either kill proliferating test experimentally the functional contribution NSPCs or to impair (or in the case of enhancing of newborn neurons to adult behavior (Deng neurogenesis to increase) the survival of new- et al. 2010). Initially, cytostatic drugs or ioniz- born neurons (Deng et al. 2010). For example, a ing irradiation impairing cell proliferation were number of different promoters were transgeni- used (and are still in use, e.g., Shors et al. 2001; cally modified to drive thymidine expres-

GCL

CA3 Hilus

Thymidin kinase Irradiation Diphteria toxin Cytostatic drugs Diphteria toxin Bax GOF WNT signaling Diphteria toxin Optogenetics

Bax KO (iBax)

Figure 1. Approaches to engineer levels of adult neurogenesis. Depicted are the developmental steps from largely quiescent radial -like neural stem cells through proliferative nonradial neural stem/progenitor cells (NSPCs) generating newborn neurons that mature and functionally integrate over the course of several weeks in the . Experimental strategies to reduce or to enhance levels act on distinct stages from the dividing NSPC to the newborn . GCL, layer; CA3, cornu ammonis area 3. (Figure courtesy of Dr. S.M.G. Braun, Brain Research Institute, Zurich, Switzerland.)

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Engineering of Adult Neurogenesis and Gliogenesis

sion in adult NSPCs that on gancyclovir (GCV) the selective expression of hyperpolarizing (or administration results in the generation of a tox- depolarizing) opsins in newborn neurons in the ic metabolite that selectively kills dividing cells adult brain (Gu et al. 2012). This represents a (Fig. 1) (Garcia et al. 2004; Saxe et al. 2006, 2007; novel and exciting tool to characterize the func- Deng et al. 2009). Most laboratories used the tional contribution of newborn neurons (Fig. regulatory elements of the nestin (coding 1). However, it is also clear that a circuitry cer- for an intermediate filament that is highly en- tainly responds “differently” to the acute silenc- riched in NSPCs) or the promoter sequences ing of neuronal populations compared with the driving glial fibrillary acidic (GFAP) situation in which this population is “missing,” (another intermediate filament that is expressed which may be the more relevant situation when in NSPCs but also in a large set of classical as- it comes to experimentally testing the role of trocytes throughout the brain). new neurons in the disease context. An inter- Using these approaches, a substantial (and esting alternative to optogenetics is the use of even complete) loss of neurogenesis can be designer receptors exclusively activated by de- achieved that is either chronic or transient (Gar- signer drugs (DREADDs) (Sternson and Roth cia et al. 2004; Deng et al. 2009). However, one 2014). For instance, virus-mediated expres- potential disadvantage of using the nestin or sion of a designer G protein-coupled receptor gfap promoter is that these regulatory sequences (hM3Dq) selectively activated by the pharma- may mediate also active sites of transgene tran- cologically inert, orally bioavailable drug cloza- scription in other somatic stem-cell compart- pine-N-oxide (CNO) allowed for assessing the ments, such as in the intestines or skin stem- ability of newborn dentate granule neurons cell niches (Bush et al. 1998; Mignone et al. to activate parvalbumin-positive 2007). The same concern holds true for nestin- (Temprana et al. 2015). or gfap-promoter-mediated deletion of survival In contrast, to the progress made over the resulting in the loss of newborn cells (Du- last decades to reduce neurogenesis, there are pret et al. 2008). An elegant approach to restrict very few tools available to enhance neurogene- cell death to the neuronal progeny of nestin-ex- sis. One elegant approach has been to delete pressing cells has been achieved by selectively proapoptotic genes selectively in adult-born expressing diphtheria toxin A (DTA) (killing cells, leading to a doubling of newborn neurons cells on expression) in nestin expression-fate- (Fig. 1) (Sahay et al. 2011). Excitingly, these mapped cells that have an active neuron-specific transgenic mice (called iBaxNes) allowed for enolase (NSE) promoter (Imayoshi et al. 2006, testing of potential gain-of-function effects of 2008). increased neurogenesis that could be indeed ex- In addition to transgenesis-based approach- perimentally observed in the behavioral context es, viral vectors have been successfully used to of -mediated pattern separation reduce levels of neurogenesis, for example, by (Sahayet al. 2011). However, a potential concern impairing proper WNT signaling (Fig. 1) (Lie with this approach may be that deletion of bax et al. 2005; Jessberger et al. 2009). Despite the increases survival of cells that would be other- advantages of high temporal and spatial control wise sorted out—by poorly understood, activi- (and the usability of rats which is advantageous ty-dependent selection criteria (Tashiro et al. for a number of behavioral experiments), there 2007). Thus, it is possible that cells are rescued is the apparent risk for off-target effects if the that do not meet certain criteria for proper in- targeted signaling pathways are not completely tegration. Thus, future approaches may target specific for NSPC/neuronal differentiation rather NSPC proliferation, allowing for subse- (e.g., WNTsignaling appears to be also involved quent proper functional selection with regard to in synaptic function/remodeling of mature survival and functional integration. neurons and not only for the generation of Be that as it may, over the last decade, im- new neurons) (Cerpa et al. 2011). Very recently, mense progress has been made to develop novel optogenetic tools have been developed allowing tools allowing for manipulating levels of neuro-

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B. Berninger and S. Jessberger

genesis and to test the functional contribution hypothesized that astroglia may perhaps retain of the resulting new neurons for adult brain some potential of generating neurons with ap- behavior. However, the specificity and temporal propriate transcriptional cues provided that control of loss- and gain-of-function will need elicit a neuronal program (Costa et al. 2010). to be further optimized to improve our under- Having shown that is required for neuro- standing how new neurons shape the functional genesis from radial glia of the , connectivity of the adult dentate circuitry in pax6 was also the first gene health and disease. tested for its capacity to reprogram early post- natal mouse astroglia into induced neurons in vitro. Indeed, forced expression of pax6 elicited ENABLING NEUROGENESIS OUTSIDE ITS a neurogenic response in these cells (Heins NATURAL NICHES et al. 2002). Using this experimental paradigm, Neurogenesis is restricted to few areas within the several studies then examined the effect of other adult brain (Zhao et al. 2006), but an unfulfilled neurogenic transcription factors, such as neu- clinical need for new neurons arises in many rog2, ascl1, dlx2, and neurod1 (Berninger et al. more brain regions in the context of human 2007; Heinrich et al. 2010; Guo et al. 2014), well disease or trauma. Although transplantation is known for their important roles during embry- potentially a viable approach to address this onic and adult neurogenesis and thus qualify- need (Lindvall 2013), here, we discuss recent ing them as potential reprogramming factors work focusing on the possibility of converting (Amamoto and Arlotta 2014). It turned out endogenous nonneuronal cells into induced that retrovirus-mediated neurog2 expression neurons (reviewed in Heinrich et al. 2015). Like- could induce in early mouse astroglia the ex- wise, a similar approach may serve to regenerate pression of a cascade of transcription factors oligodendroglia for those disease scenarios in (Tbr2 and Tbr1) that hallmark glutamatergic which this cell type degenerates. neurogenesis (Berninger et al. 2007) and con- vert these into fully functional synapse-form- ing neurons of glutamatergic neuron identity Reprogramming of Central (Heinrich et al. 2010). This very same astroglia (CNS) Glia into Induced Neurons could be reprogrammed into neurons of the One of the earliest studies in this direction was GABAergic lineage by forced expression of work by Kondo and Raff showing that sequen- ascl1 or dlx2. This data thus show that a single tial exposure to specific extracellular signals transcription factor suffices to reprogram early could reprogram precursor postnatal into functional neurons. cells (OPCs) to multipotential CNS (central But recent work indicates that even in culture, nervous system) stem cells (Kondo and Raff astrocytes quickly lose their permissiveness 2000). It was recognized that this reprogram- to single transcription factor reprogramming ming is accompanied by chromatin remodeling (Maserdotti et al. 2015). Five days after exposure resulting in the reactivation of the gene to differentiating conditions, astrocytes derived (Kondo and Raff 2004), a key transcription fac- from mouse postnatal cortex no longer repro- tor in neural stem cells, but also of pivotal im- gram following induced Neurog2 expression. portance during reprogramming toward pluri- This loss of reprogramming permissiveness ap- potency (Sarkar and Hochedlinger 2013). pears to be mediated by REST (RE-1 silencing Based on the recognition that neural stem transcription factor), which prevents Neurog2 cells both during development and in the adult of binding to its target sites. However, failure of have a radial glia identity sharing many mol- reprogramming can be bypassed by directly ac- ecular and cellular features with parenchy- tivating some of the Neurog2 targets, such as mal astrocytes (Doetsch et al. 1999; Malatesta NeuroD4. This data then support the notion et al. 2000; reviewed in Kriegstein and Alvarez- that reprogramming permissiveness is strongly Buylla 2009), Magdalena Go¨tz and colleagues dependent on the epigenetic state of the cells to

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Engineering of Adult Neurogenesis and Gliogenesis

be lineage-converted. Likewise, the highly dif- response that requires deattachment from mi- ferent permissiveness of fibroblasts and kerati- crovessels to which these cells are associated un- nocytes to Ascl1-induced reprogramming ap- der healthy conditions (Goritz et al. 2011). In pear to be consequence of their specific and addition to glial cells, such “reactive” pericytes distinct chromatin signature at Ascl1 targets may represent an interesting target for in vivo (Wapinski et al. 2013). After all, this leads to reprogramming (Karow et al. 2012). the, probably not very surprising, conclusion that cells that have undergone considerable epi- genetic maturation will prove hardest to repro- In Vivo Reprogramming in the Adult Brain gram (Fig. 2). Attempts of direct lineage reprogramming of Thus, it is encouraging that the adult hu- glial cells into neurons have now been carried man brain does contain cells that appear to be on to the in vivo level in the cerebral cortex, amenable to reprogramming into induced neu- , and (Buffo et al. 2005; rons. Aiming at converting cells isolated from Grande et al. 2013; Guo et al. 2014; Heinrich biopsies, we identified cells ex- et al. 2014). Already, an early study from the pressing a battery of pericytic markers in vitro Go¨tz laboratory addressed the possibility of that can be converted following combined ex- converting proliferative cells in the injured ce- pression of sox2 and ascl1 (Karow et al. 2012). rebral cortex into induced neurons and found Here, as in maturing astrocytes, the proneural that expression of Pax6 or repression of Olig2 gene (ascl1) alone fails to reprogram, suggesting transcriptional targets resulted in the transient that the effect of sox2 coexpression may con- emergence of (DCX)-positive sist in rendering Ascl1 targets more accessible cells (Buffo et al. 2005). More recently, it was (see discussion below). Interestingly, pericytes found that in the injured cerebral cortex in emerge as new players in CNS scar formation, a vivo fate conversion of nonneuronal cells by

Astrocytes Sox2 Pax6 GABAergic Astrocytes NeuroD1 Ascl1 neurons Sox2 Ascl1 Neurons Pericytes Glutamatergic neurons iNs Ngn2 Astrocytes Cortex Sox2 Pericytes Capillary Neurons

CPN Fezf2 Striatum CFPN

Astrocytes SMN Ascl1 Fezf2 Brn2 Myt1l CFPN Neurons

Figure 2. Engineering neurogenesis outside the classical neurogenic niches. Depicted are the different in vitro and in vivo approaches scrutinized so far for reprogramming nonneuronal cells into induced neurons. Likewise, highlighted are in vivo experiments assessing the possibility of converting distinct types of neuronal progenitors or neurons into another via in utero electroporation. MSN, medium spiny neuron; CPN, callosal projection neuron; CFPN, corticofugal projection neuron. (Figure courtesy of Dr. M. Karow, Institute of Physiology, LMU Munich, Germany.)

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B. Berninger and S. Jessberger

neurogenic fate determinants can be influenced trophic factor (BDNF) and the natural bone by simultaneous delivery of growth factors morphogenetic protein (BMP) inhibitor noggin (Grande et al. 2013). However, in both studies, or treated with a histone deacetylase inhibitor. the precise cellular source of the induced neu- Of note, we found that forced sox2 expression ronal cells remained unknown. can also convert reactive glia in the cerebral cor- Previously, pioneering work from the Wer- tex of mice following stab wound injury (Hein- nig laboratory had shown that three factors, rich et al. 2014). Remarkably, this effect was ascl1, brn2, and myt1l, can reprogram fibro- strictly dependent on prior injury suggesting blasts into induced neurons (Vierbuchen et al. that the lesioning rendered the cells more per- 2010). Torper et al. (2013) now delivered this missive to glia-to-neuron conversion. Moreover, factor triad into the adult striatum via cre-in- to our surprise, genetic fate mapping revealed ducible lentiviral vectors. Indeed, they found that the cell population undergoing fate con- NeuN-positive cells that were also reporter-pos- version was not the astrocytic compartment itive (an indicator of recombination) in a trans- but NG2 glia. Despite the fact that the physio- genic mouse line expressing cre under control of logical role of these cells in grey matter is still regulatory elements of the gfap gene (gfap-cre), largely enigmatic, they can function as oligo- providing evidence for direct -to-neu- dendrocyte progenitor cells (Dimou and Gotz ron conversion in situ (Fig. 2). With a caveat for 2014). Hence, it might be possible that it is their some leakiness of gfap promoter activity, this status as progenitors that renders these cells study provided compelling evidence for an as- more permissive to lineage conversion. Finally, troglial origin of the reprogrammed cells. How- this work confirmed the neurogenic effect of ever, it remains unknown whether the virus- Sox2 first reported by Niu et al. (2013). Al- targeted glial cells were reactive (as a response though this is somewhat puzzling, given the to the virus injection) or nonreactive parenchy- classical role of Sox2 as a stem-cell maintenance mal astrocytes. In fact, recent work from the factor, recent work also shows that it primes Frise´n laboratory has suggested that striatal as- the epigenetic landscape in adult hippocampal trocytes possess a latent neurogenic program, progenitors for expression of neurogenic genes under healthy conditions restrained by Notch (Amador-Arjona et al. 2015). Perhaps Sox2 does signaling, but unleashed following injury (Mag- the same work also in the above-described re- nusson et al. 2014). programming scenarios. In contrast, a recent study from the Zhang Finally, the Chen laboratory made the very laboratory has provided evidence that forced surprising observation that retrovirus-mediated expression of sox2 alone can drive striatal astro- NeuroD1 alone was sufficient to drive reactive cytes (as evidenced by several lines of genetic astroglia and NG2 glia (using gfap and NG2 fate-mapping experiments) toward early stages promoter-controlled retroviral vectors) of the of neurogenesis (Fig. 2) (Niu et al. 2013). Sur- adult mouse cerebral cortex with unprecedent- prisingly, these data suggest that the repro- ed efficiency toward neurogenesis in the ab- grammed cells do not acquire a neural-stem- sence of additional injury, besides that caused cell identity (as evidenced by absence of nestin by virus injection, and the induced neurons expression at any stage), as one might have ex- fairly rapidly developed remarkable electro- pected at first glance, given the known role of physiological properties (Guo et al. 2014). Giv- sox2 in neural stem cells. Nonetheless, these en the emerging concept that glial cells acquire cells incorporated bromodeoxyuridine (BrdU) stem-cell-like properties following injury (Di- and apparently proliferated as DCX-positive mou and Gotz 2014), it will be of obvious . Although these cells fail to acquire interest to assess the contribution of the virus a mature neuronal state when left alone, they injection-induced injury, if any, to the repro- develop into postmitotic neurons with remark- gramming process. able electrophysiological properties when ex- An altogether different approach developed posed to the brain-derived neuro- by the Arlotta laboratory aims at reprogram-

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Engineering of Adult Neurogenesis and Gliogenesis

ming one neuron type into another. Rouaux the identity of cells, it remains to be explored and Arlotta (2010) showed that striatal progen- whether the new phenotype corresponds to a itors that normally give rise to medium spiny “real” identity or rather reflects a chimeric state. neurons can be reprogrammed into pyramidal- Transcriptome studies of direct reprogrammed like neurons on forced expression of the tran- fibroblasts typically emphasize the similarity scription factor Fezf2 (Fig. 2). Remarkably, these between the induced and naturally born neu- neurons can project to subcortical targets, in- rons, but, nonetheless, cannot but acknowledge cluding the spinal cord, consistent with the differences that appear to be the more pro- role of Fezf2 in imposing a corticofugal projec- nounced the more terminally differentiated tion neuron identity. This Fezf2 effect extends the cell of origin has been (Marro et al. 2011). into early postmitotic life, as illustrated by the This notion is of great significance when poten- fact that callosal projection neurons can still be tially considering reprogramming strategies converted into corticofugal neurons during the within the adult human brain in which most first postnatal days, but lose such potential on cells are postmitotic, possibly with exception closure of a critical, molecularly not-yet-de- of slowly cycling OPCs (Yeung et al. 2014). fined window of nuclear plasticity (Rouaux The precise mechanisms underlying repro- and Arlotta 2013). A key question will be how gramming are still poorly understood. A study to reopen this window of plasticity, evidently in fibroblasts revealed that ascl1-induced con- imposed by epigenetic modification in the version into neurons relies on this transcription course of cell differentiation. One exciting pos- factor’s capacity of accessing closed chromatin, sibility may be to render these cells capable of but only when these loci are in a defined triva- undergoing cell proliferation. Although this lent state (as defined by specific active and sounds a priori violating the fact that neurons repressive histone modifications), reprogram- are per definition postmitotic entities, studies in ming can occur (Wapinski et al. 2013). How- the adult heart have shown that bona fide post- ever, it remains unclear whether any of the non- mitotic cells can be enticed to enter cell cycle neuronal cells retain such trivalent state into without losing their cellular specification even adulthood, especially in aged human beings, in vivo on expression of specific microRNAs in which the need for new neurons may become (Eulalio et al. 2012). It will be of great intellec- most pressing. If the molecular underpin- tual and technical value to learn whether post- nings of reprogramming are still ill understood, mitotic neurons are susceptible to similar ma- even more mysterious is how morphologically nipulations. complex cells will metamorphose into neu- rons. Considering the tremendous complexity of adult human astrocytes (Oberheim et al. Future Perspectives of Engineering 2009), it will be fascinating to see how these cells Neurogenesis Outside Physiological remodel their astrocytic process into neuronal Neurogenic Niches ones, an issue perhaps to be addressed by two- Although the above-discussed findings provide photon live imaging in models of cortical repro- strong evidence for the principal possibility gramming, which allow for the access required of engineering neurogenesis in regions of the for in vivo imaging. Yet, given that rather com- adult brain, which lack any physiologically rel- plex radial glial cells manage to generate neu- evant degree of neuron production, the ques- rons (Noctor et al. 2001), it may not be entirely tion remains to what extent this will enable us to hopeless that other cells of equal complexity utilize reprogramming strategies for brain re- could achieve this. Live imaging could also re- pair. There are several issues to be dealt with veal crucial information as to whether re- before we can realistically hope to translate the programming takes place directly, as suggested experimental studies into a clinical context. by in vitro studies (Heinrich et al. 2010), or First of all, although reprogramming tran- requires proliferation. After all, a proliferative scription factors are powerful tools to change metamorphosis may ultimately allow for asym-

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B. Berninger and S. Jessberger

metric cell division, by which not only a new a conducive microenvironment (Heinrich et al. neuron may be generated but ideally a cell of the 2015). original identity regenerated, thus avoiding de- pletion of functionally important cells. DIRECTED DIFFERENTIATION OF ADULT A further challenge concerns the issue of NEURAL STEM CELLS functional integration into the neuronal circuit- ry. Functional integration may indeed be a pre- The focus on targeted engineering of endoge- requisite for long-term survival (Tashiro et al. nous NSPCs (or cells that do not generate neu- 2006). Although early data suggest that induced ronal cells under physiologically conditions) neurons derived from in vitro as well as in vivo has been to enhance the generation of neurons reprogrammed cells exhibit electrical properties or to induce neuronal differentiation. However, of neurons, receive synaptic input, and, at least diseases of the CNS obviously also affect the in vitro, are capable of generating synaptic out- functional integrity or lead to a loss of glial put, it remains to be shown whether these cells cells. Given this, especially the NSPC-derived incorporate in a meaningful manner. Failure to generation of , that are, for ex- do so may not only compromise their chances ample, disease targets in chronic demyelinating for survival, but compromise circuit function. diseases such as MS, has gained significant Many neurological diseases are recognized to attention (Jadasz et al. 2012). Notably, NSPCs be caused by defects in connectivity that may in the SVZ generate oligodendrocytes under be as severe as in epilepsy or more subtle like physiological conditions, and the formation of in autism or schizophrenia. In this context, phy- oligodendrocytes is enhanced after demyelinat- siological adult neurogenesis may serve as a ing lesions (Menn et al. 2006; Xing et al. 2014). model of how new neurons are incorporated Thus, the identification of signaling pathways to smoothly modify circuit function. The stud- that mediate oligodendrocytic differentiation ies of the Song laboratory have shown the im- is important and may lead to the development portant “chaperone” role of parvalbumin-pos- of novel strategies to enhance oligodendro- itive interneurons for regulating genesis and genesis in the context of demyelinating disease differentiation of adult-born dentate granule (Fig. 3). This is true for the recently identified neurons (Ge et al. 2006; Song et al. 2012, role for WNT signaling to expand the NSPC- 2013). More generally, integration takes place derived oligodendrocytic lineage, the up-reg- in a very orderly fashion (Deshpande et al. ulation of chordin that directs cells toward an 2013), suggesting that integration is a process oligodendrocytic fate on demyelination in the of reciprocity between new neurons and pre- corpus callosum, and for the finding that loss existing circuitries. Incorporation of induced of SIRT1 enhances oligodendrogenesis (even neurons derived from reprogrammed cells is though it remains unclear whether the en- likely to require similar interactions with chap- hanced generation of oligodendrocytes on loss erone cells. of SIRT1 depends on NSPCs) (Fig. 3) (Jablon- Finally,for most neurodegenerative diseases, ska et al. 2010; Ortega et al. 2013; Rafalski et al. such as Alzheimer’s disease, stroke and multiple 2013). sclerosis (MS), do not affect single cell types The situation in the hippocampal stem-cell in clean isolation, but involve the entire ner- niche is distinct compared with the SVZ as only vous tissue comprising neurons, glia, , very few (if any) oligodendrocytes are generated and blood-borne immune cells, reprogramming under normal conditions (Zhao et al. 2006). may not be a viable strategy for brain repair after However, it has been recently shown that the all, if this does not take into account the micro- fate of newborn cells can be redirected from a environmental changes, such as, for example, neuronal toward an oligodendrocytic fate by the the inflammatory response that these diseases overexpression of the basic helix–loop–helix induce. Thus, reprogramming strategies must (bHLH) transcription factor ascl1 (Fig. 3) (Jess- go hand in hand with interventions that create berger et al. 2008). Even though induced oligo-

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Engineering of Adult Neurogenesis and Gliogenesis

Viral overexpression of Ascl1

Chordin- mediated signaling

Neuron NSC RMS DG OB SVZ

Manipulating Manipulating SIRT1 activity WNT signaling

Figure 3. Mechanisms to direct the differentiation of endogenous neural stem/progenitor cells (NSPCs). Shown are several experimental strategies to enhance neural subtype specific differentiation (e.g., through modulating WNTsignaling) or to direct the fate of newborn cells from a neuronal toward the glial lineage (e.g., through ascl1 overexpression in hippocampal NSPCs; shown in the left inset). NSC, Neural ; DG, dentate gyrus; SVZ, ; RMS, ; OB, . (Figure courtesy of Dr. S.M.G. Braun, Brain Research Institute, Zurich, Switzerland.)

dendrogenesis appears to be capable to generate in the form of specific transcription factors , it remains unclear whether newborn that instruct the genesis of all the plethora of oligodendrocytes generated through directed neuronal and glial subtypes to recreate for in- differentiation turn out to be sufficient to en- stance a piece of infarcted cortex? Here, we can hance remyelination in the context of injury open only a highly speculative window into the (Goldman and Natesan 2008; Jessberger and solution by referring to the remarkable degree Gage 2009). of self-organization that neural stem cells de- However, focusing the attempts to generate rived from embryonic stem cells exhibit when functional glial cells—in addition to enhanced exposed to an appropriately permissive envi- or induced generation of neurons—will cer- ronment eventually resulting in the formation tainly be of growing interest over the next year of cerebral organoids (Kadoshima et al. 2013; but will require the development of novel tools Lancaster et al. 2013). Too little is known of to faithfully control the generation of glial cells the underlying logic of this self-organizing pro- within the adult brain. cess, but the fact that somatic cells such as fibro- blasts can be reprogrammed into multipotent neural-stem-cell-like cells (Lujan and Wernig FUTURISTIC BRAIN REPAIR 2012) gives some cause for hope that this may In some of the most devastating brain diseases ultimately go along with gaining not only the like Alzheimer or stroke, it is not just a single capacity for neuro- but even “cerebrogenesis.” type of neuron that degenerates but an entire circuit that needs to be replaced. How to rebuild SUMMARY such highly structured assemblies of neurons (and glia) by reprogramming? Will it be re- Injury to the adult CNS, through acute or quired to provide point-by-point instructions chronic disease, often results in the loss or func-

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tional impairment of neuronal and/or glial tion modulate learning and memory in the brain. J Neu- cells. Recent advances indicated the possibility rosci 29: 13532–13542. Deng W, Aimone JB, Gage FH. 2010. New neurons and new to engineer the fate and potency of NSPCs memories: How does adult hippocampal neurogenesis or other resident cells to serve as a source for affect learning and memory? Nat Rev Neurosci 11: 339– cell replacement of lost structures, opening nov- 350. el possibilities in the context of regenerative Deshpande A, Bergami M, Ghanem A, Conzelmann KK, Lepier A, Go¨tz M, Berninger B. 2013. Retrograde mono- medicine. However, most approaches currently synaptic tracing reveals the temporal evolution of inputs pursued require invasive strategies to genetically onto new neurons in the adult dentate gyrus and olfac- modify adult brain cells for fate direction or tory bulb. Proc Natl Acad Sci 110: E1152–E1161. reprogramming, indicating that these highly Dimou L, Go¨tz M. 2014. 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Engineering of Adult Neurogenesis and Gliogenesis

Benedikt Berninger and Sebastian Jessberger

Cold Spring Harb Perspect Biol 2016; doi: 10.1101/cshperspect.a018861 originally published online April 18, 2016

Subject Collection Neurogenesis

Adult Neurogenesis and Psychiatric Disorders Adult Olfactory Bulb Neurogenesis Eunchai Kang, Zhexing Wen, Hongjun Song, et al. Pierre-Marie Lledo and Matt Valley Neuronal Circuitry Mechanisms Regulating Adult Adult Neurogenesis in Fish Mammalian Neurogenesis Julia Ganz and Michael Brand Juan Song, Reid H.J. Olsen, Jiaqi Sun, et al. Neurogenesis in the Developing and Adult Brain In Vitro Models for Neurogenesis −−Similarities and Key Differences Hassan Azari and Brent A. Reynolds Magdalena Götz, Masato Nakafuku and David Petrik Genetics and in Adult Neurogenesis Engineering of Adult Neurogenesis and Jenny Hsieh and Xinyu Zhao Gliogenesis Benedikt Berninger and Sebastian Jessberger The Adult Ventricular−Subventricular Zone Computational Modeling of Adult Neurogenesis (V-SVZ) and Olfactory Bulb (OB) Neurogenesis James B. Aimone Daniel A. Lim and Arturo Alvarez-Buylla Diversity of Neural Precursors in the Adult Control of Adult Neurogenesis by Short-Range Mammalian Brain Morphogenic-Signaling Molecules Michael A. Bonaguidi, Ryan P. Stadel, Daniel A. Youngshik Choe, Samuel J. Pleasure and Helena Berg, et al. Mira Detection and Phenotypic Characterization of Adult Neurogenesis: An Evolutionary Perspective Adult Neurogenesis Gerd Kempermann H. Georg Kuhn, Amelia J. Eisch, Kirsty Spalding, et al. Maturation and Functional Integration of New Epilepsy and Adult Neurogenesis Granule Cells into the Adult Hippocampus Sebastian Jessberger and Jack M. Parent Nicolas Toni and Alejandro F. Schinder

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