Lupo G.

Piper M.

Zolessi F. R.

English

Archivio della ricerca- Università di Roma La Sapienza

EDITORIALpublished: 13 April 2021doi: 10.3389/fcell.2021.678475Frontiers in Cell and Developmental Biology | www.frontiersin.org 1 April 2021 | Volume 9 | Article 678475Edited and reviewed by:Valerie Kouskoff,The University of Manchester,United Kingdom*Correspondence:Giuseppe Lupogiuseppe.lupo@uniroma1.itMichael Piperm.piper@uq.edu.auFlavio R. Zolessifzolessi@fcien.edu.uySpecialty section:This article was submitted toStem Cell Research,a section of the journalFrontiers in Cell and DevelopmentalBiologyReceived: 09 March 2021Accepted: 22 March 2021Published: 13 April 2021Citation:Lupo G, Piper M and Zolessi FR(2021) Editorial: Context-DependentRegulation of Neurogenesis: CommonThemes and Unique Features of theNeurogenic Process in Different ModelSystems.Front. Cell Dev. Biol. 9:678475.doi: 10.3389/fcell.2021.678475Editorial: Context-DependentRegulation of Neurogenesis:Common Themes and UniqueFeatures of the Neurogenic Processin Different Model SystemsGiuseppe Lupo 1*, Michael Piper 2* and Flavio R. Zolessi 3,4*1Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Rome, Italy, 2 School of BiomedicalSciences, The University of Queensland, Brisbane, QLD, Australia, 3 Sección Biología Celular, Facultad de Ciencias,Universidad de la República, Montevideo, Uruguay, 4 Institut Pasteur de Montevideo, Montevideo, UruguayKeywords: neurogenesis, neurogenic niche, neural stem/progenitor cells, neuronal differentiation, in vitro andin vivo models, model organismsEditorial on the Research TopicContext-Dependent Regulation of Neurogenesis: Common Themes and Unique Features of theNeurogenic Process in Different Model SystemsDuring neural development, neural stem/progenitor cells (NSPCs) proliferate to self-renew andgenerate progeny that undergo neuronal differentiation, a process known as neurogenesis. In manyorganisms, this process is temporally restricted and mostly limited to embryonic and early post-natal development, although adult neurogenesis also takes place in a region-specific and species-specific manner. In the developing nervous system, NSPCs produce region-specific amounts andtypes of neurons, following distinct temporal schedules, according to their positional identity andthe extracellular environment to which they are exposed; these differences are key to shape theanatomical and functional properties of different neural structures, and to ensure proper wiringof complex neuronal networks. Moreover, in adult life, differences in positional information,developmental history, and extrinsic cues across the nervous system determine whether or notspecific neural structures are capable of continued neurogenesis, as well as the quantity and the fateof adult born neurons.Over the years, molecular studies have shown that the core mechanisms driving NSPC self-renewal and neuronal differentiation are remarkably conserved in organisms as different as fliesand mice. At the same time, the transcriptional programs expressed in NSPCs, as well as theextracellular signals acting upon them in the neurogenic niche, can change substantially in differentorganisms, or even in different regions or stages within the same organism. This context-dependentregulation of neurogenesis confers unique properties to each neurogenic niche and its neuronaloutput. Grasping both the shared and the unique mechanisms underlying NSPC function andneurogenesis in different contexts may crucially improve our understanding of how the exceptionalcellular, anatomical, and functional complexity of the human brain is achieved and maintained inthe developing and adult organism. It would also be paramount to the development of experimentalmodels that faithfully recapitulate this complexity in vitro, and of cell therapies for the treatmentof neurodevelopmental and neurodegenerative conditions affecting the nervous system in differentregions and ages.This Research Topic addresses both the fundamental mechanisms of neurogenesis that areconserved in different model systems, and the peculiar traits that distinguish different neurogenicLupo et al. Editorial: Context-Dependent Regulation of Neurogenesisniches from each other, by assembling a remarkable collectionof articles written by leading experts in the field. Severalof the main model organisms employed in developmentalneuroscience are represented in this Research Topic, whichincludes: (i) key experimental paradigms both in the centraland peripheral nervous system (CNS, PNS); (ii) embryonicand adult neurogenesis; (iii) in vitro and in vivo models. Abrief introduction to the articles in this Research Topic isprovided below.Neural development relies on the proliferation anddifferentiation of NSPCs to be regulated spatially and temporallyin a context-dependent manner such that discrete structurescan be formed. This is perhaps most clearly exemplified inthe mammalian cerebral cortex. This region of the brainhas undergone extensive expansion within the mammalianlineage, especially within primates. Understanding how thetranscriptional architecture within NSPCs of the anterior brainhas changed to facilitate expansion of the neocortex, and howthis program has diversified within different mammalian lineagesis reviewed by Franchini. This review encompasses researchthat has asked key questions about neocortical development,including how the neocortex emerged, and how it is differentin comparison to brain development in other tetrapods, howthe 6-layered structure of the neocortex evolved, and howit is generated, the mechanism and underlying control ofcortical gyrification, and the importance of interneurons forcortical function.Development of the neocortex also requires the coordinationof a range of signals, both intrinsic and extrinsic, in NSPCs.For example, Shohayeb et al. describe the role of the spindlemicrotubule-associated phosphoprotein WDR62 in regulatingthe proliferation of NPSCs within the developing mouse cerebralcortex. The importance of WDR62 for cortical neurogenesis isunderscored by the fact that mice lacking this factor exhibitmicrocephaly. Conversely, Cao et al. used cultured NSPCsfrom embryonic rat cerebral cortices to demonstrate that theintravenous anesthetic propofol mediates cell-extrinsic effects onNSPCs, impacting their differentiation. Given the widespreaduse of propofol, studies such as this are key to understandinghow such anesthetics can be safely used. Finally, Xing andHuttner review our understanding of how neurotransmitterswithin the developing mammalian neocortex serve to regulateNSPC proliferation. This review, as well as a review byShou et al., also discuss the use of organoids to understandbrain development and better define our understanding ofneurological diseases. Given that research on the humanbrain has traditionally been hampered by a paucity of tissue,organoids have emerged as a powerful tool to probe the cellular,molecular, and genetic factors underpinning the developmentof many regions of the human brain, including the cerebralcortex. Although research has faced issues relating to highvariability between organoids, standardization of techniques andprotocols is gradually emerging. This has enabled researchersto better understand normal development, as well as to modelneurodevelopmental disorders such as primary microcephaly,lissencephaly, and autism in a human context. While challengesremain with organoid technology, such as whether thesestructures will ever be able to truly reflect the complexity ofthe human brain, they offer another lens through which thedevelopment of the brain can be modeled and tested.Because of its anatomical accessibility and simplicity, thevertebrate neural retina has long been a preferred CNS areafor studying neurogenesis. Three articles of this ResearchTopic address important aspects of retinal neurogenesis. RetinalNSPCs, like those in other areas of the CNS, are organized inthe tight and highly polarized pseudo-stratified neuroepithelium,and they undergo interkinetic nuclear migration as theyproliferate. Clark et al. concentrated on the characterizationof a particular mechanism influencing the balance betweenproliferation and neurogenesis of retinal NSPCs in the zebrafishembryo, namely the apical localization of a Crumbs familymember, Crb2a, depending on the endocytic pathway regulatorRab11a. The generation of a structured and functional retina doesnot only depend on the balance of proliferation and neurogenesis,since a third player affects the outcome of both processes:apoptosis. This can be physiological, occurring during normaldevelopment to adjust neuron number, or pathological, inrelation to neurodegeneration. Trying to understand the possiblerole of DNA damage on retinal degeneration, Gomes et al.inactivated the gene encoding the Rad50 partner protein Rint1specifically in mouse retinal NSPCs, showing that, instead ofcausing a proliferation halt by activating the cell cycle checkpoint,this mutation, and the DNA breaks it caused, drove the cellstoward apoptosis. Helping to join these two concepts together,the Perspective Article by Oliveira-Valença et al. provides anexcellent discussion of an important biomedical issue whoseresolution might lie in a better understanding of the basicmechanisms of embryonic neurogenesis: the degeneration of theprojection neurons in the retina, retinal ganglion cells, in veryprevalent human eye diseases such as glaucoma.In addition to looking at general mechanisms affectingneurogenesis in whole areas of the nervous system, like theabove-described mammalian cortex or the vertebrate retina,there are other levels of analysis. On the one hand, it is importantto look at the cellular and subcellular level, where mechanismstend to be more general across species, organs, and neuronaltypes. Two reviews in this Research Topic address the importantroles of membrane dynamics in neurogenesis. Moore et al. givea brief but essential account on the recently expanding fieldin cell signaling based on cell protrusions, including filopodiaand cytonemes. Interestingly, in addition to secreted paracrinefactors, able to diffuse for a variable distance across tissues,and contact between immediate neighboring cells, an increasingnumber of reports are indicating the presence of a diverse rangeof cell processes having roles in neurogenesis, such as the onesdescribed here mediating Notch lateral inhibition. Studying themorphological polarization and early differentiation of neurons,Rozes-Salvador et al. analyse the role of intracellular membranetraffic, asmodulated by different small GTPases, including Rab11,in neurite outgrowth. On the other hand, a close look into themolecular players regulating the generation and differentiationof one specific cell type is usually very enlightening, as in thecase of the review article by Yang et al. on the specification ofthe enigmatic Kolmer-Agduhr interneurons of the spinal cord ofFrontiers in Cell and Developmental Biology | www.frontiersin.org 2 April 2021 | Volume 9 | Article 678475Lupo et al. Editorial: Context-Dependent Regulation of Neurogenesisdifferent vertebrate species, whichmaintain an apical border witha primary cilium toward the ependymal canal.A different paradigm in vertebrate embryonic neurogenesisis represented by the PNS. In this case, neurons do not arisefrom the neural tube neuroepithelium, but from cells at theneural plate border (the neural crest; NC) or cranial ectodermalplacodes, from which they undergo an epithelial to mesenchymaltransition and migrate to eventually populate the peripheralganglia. Two extensive and complementary reviews discuss theorigin, (Mendez-Maldonado et al.), the structural organization(Vermeiren et al.), and the transcription factors involved inneuronal specification (both reviews), of cranial ganglia, whilea very interesting research article analyses some of the signalsinvolved in the generation of a set of neurons in the basalchordate Ciona (a group lacking NC), which are homologous todorsal root ganglion neurons (Kim et al.). A special case in thecranial PNS is the olfactory organ, where neurons are themselvesexposed to the environment, and are hence expected to be a verysensitive portion of the nervous system to pathogen invasion.In their research report, Palominos and Whitlock explore therelationship between neurogenesis and immune cells in the earlydevelopment of the olfactory organ in zebrafish.Following its discovery in mammals, which were thoughtto generate all their brain neurons during development, adultneurogenesis has become a major focus of neuroscienceresearch, given its involvement in brain plasticity and inneuropathological conditions, and the hope of harnessing itfor therapeutic purposes. Since adult NSPCs originate fromsubpopulations of embryonic NSPCs, and their propertiesare largely rooted in their developmental history, theneed for an integrated view of developmental and adultneurogenesis is increasingly appreciated, as reviewed by Miraand Morante. Focusing on flies and mice, these authorsillustrate how the types of cell division and cell interactionsused by NSPCs are key to generate neuronal diversity duringdevelopment and for continued neurogenesis in the adultbrain, and how they are influenced by intrinsic transcriptionalprogrammes and extrinsic cues, highlighting the role of nicheglial cells.Although the process of adult neurogenesis has primarilybeen studied in rodents, other vertebrate models may provideimportant insights. Labusch et al. review recent progress inthe study of adult neurogenesis in zebrafish, discussing how,thanks to adult neurogenic niches easily accessible to liveimaging, this organism is allowing to dissect adult NSPCheterogeneity and cell cycle dynamics to a detail difficult toachieve in mammals. Several properties of mammalian adultNSPCs, including their responsiveness to various stimuli, canbe recapitulated in zebrafish, and the regenerative capacityof zebrafish neurogenesis may help to understand the lackof regeneration in the mammalian brain. The importance ofexploiting the advantages of non-mammalian model systems isalso evident in the work of Naef et al., who employed Xenopusembryos to show thatMex3A, a gene associated with brain aging,is a crucial regulator of NSPC proliferation.Two reviews focus on classical paradigms of adultneurogenesis in mice: the hippocampal dentate gyrus andthe subventricular zone of the lateral ventricles. Bonafinaet al. discuss the complexity of the extrinsic cues acting in thehippocampal niche, and the need to further understand howdifferent cues are integrated by NSPCs and/or modulate specificNSPC subpopulations. Ceccarelli et al. examine the effects thatvarious physiological and pathological stimuli exert on adultNPSC proliferation, and their interactions with the geneticprogrammes controlling the NSPC cell cycle. The authorshighlight recent studies showing that appropriate combinationsof neurogenic stimuli and genetic modifications can recruitquiescent NSPCs into the cell cycle even in the aged brain,suggesting that the adult NSPC pool may be more resilient toexhaustion than previously believed.Altogether, this Research Topic provides an updated view ofneurogenesis in different regions, stages and organisms, whichwe hope will be valuable to foster further investigation of thisfundamental process and its physio-pathological implications.AUTHOR CONTRIBUTIONSGL, MP, and FZ equally contributed as Guest Editors of thisResearch Topic and closely interacted throughout the editorialprocess, by defining the subjects to be treated and inviting leadersin specific research fields to contribute their work, and by actingas handling editors of all the manuscripts submitted to theResearch Topic and writing the Editorial. All authors contributedto the article and approved the submitted version.FUNDINGGL was supported from research project grants from SapienzaUniversity of Rome. MP was supported by an AustralianResearch Council (ARC) Discovery Project (DP180100017). FZwas supported by PEDECIBA and Dedicación Total, UdelaR.ACKNOWLEDGMENTSWe thank the Editorial Office of Frontiers in Cell andDevelopmental Biology for their assistance throughout theeditorial process.Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Copyright © 2021 Lupo, Piper and Zolessi. This is an open-access article distributedunder the terms of the Creative Commons Attribution License (CC BY). The use,distribution or reproduction in other forums is permitted, provided the originalauthor(s) and the copyright owner(s) are credited and that the original publicationin this journal is cited, in accordance with accepted academic practice. No use,distribution or reproduction is permitted which does not comply with these terms.Frontiers in Cell and Developmental Biology | www.frontiersin.org 3 April 2021 | Volume 9 | Article 678475

Editorial: Context-Dependent Regulation of Neurogenesis: Common Themes and Unique Features of the Neurogenic Process in Different Model Systems

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Editorial: Context-Dependent Regulation of Neurogenesis: Common Themes and Unique Features of the Neurogenic Process in Different Model Systems

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