Evolution and Ecology
Evolution and Ecology BIOL 3020
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REVIEW 3771 Development 134 37713780 2007 doi 10 1242dev 006379 Spatial and temporal specification of neural fates by transcription factor codes Francois Guillemot The vertebrate central nervous system contains a great diversity of neurons and glial cells which are generated in the embryonic neural tube at specific times and positions Several classes of transcription factors have been shown to control various steps in the differentiation of progenitor cells in the neural tube and to determine the identity ofthe cells produced Recent evidence indicates that combinations of transcription factors of the homeodomain and basic helixloophelixfamilies establish molecular codes that determine both where and when the different kinds of neurons and glial cells are generated Introduction A multitude of neurons of different types as well as oligodendrocytes and astrocytes see Box 1 are generated as the vertebrate central nervous system develops These different neural cells are generated at de ned times and positions by multipotent progenitors located in the walls of the embryonic neural tube Progenitors located in the ventral neural tube at spinal cord level first produce motor neurons Wthh 39 1 1 1 111 1 1 l 1 v 1 1 Fig l The first cells produced by progenitors at more dorsal or ventral positions in the spinal cord are intemeurons of different classes The generation of a particular class of neuron or glial cell from a multipotent progenitor is a complex process that can be subdivided into a series of sequential steps Fig 2AB First progenitor cells acquire unique positional identities through a process of spatial patterning of the neural primordium Thus progenitors in the ventral spinal cord that produce motor neurons and oligodendrocytes acquire a distinct identity from that of progenitors 39n the dorsal spinal cord or brain Multipotent progenitors then produce daughter progenitor cells that are restricted to produce only one of e primary neural cell types 7 neurons oligodendrocytes or astrocytes 7 in a step called cell type selection or commitment Committed neuronal progenitors also become specified to produce neurons of aparticular kind eg a particular class of motor neuron or interneuron a step called subtype specification that is conceptually distinct from but mechanistically tightly linked to the step of cell type commitment as we will see Neuronal progenitors then stop dividing migrate out of the re enitor zones they occupy see Fig 1B and towards more differentiated arws of the neural tube There they initiate a programme of terminal differentiation Oligodendrocytes astrocytes and some types of neurons begin to migrate and differentiate while still dividing The fact that particular classes of neurons and glial cells are produced only at particular locations in the embryonic neural tube suggests that the mechanisms that govern spatial patterning and the acquisition of diverse cell fates are linked Moreover neurons and glial cells are produced in a defined order first neurons then oligodendrocytes then astrocytes and different classes of neurons National institute for Medical Research The Ridgevvay Mill Hill NW7 1AA London UK ermail fguillenimrmrc ac uk Box 1 Neurons and glial cells Neuron Oligodendrocyte Astrocyte The vertebrate central nervous system comprises three primary cell types including neurons and two types of glial cells Neurons are electrically eXCitable cells that process and transmit information Via the release of neurotransmitters at synapses Different subtypes of neurons can be distinguished by the morphology of their cell body and dendritic tree the type of cells they connect With Via their axon the type of neurotransmitter used etc The two main types of glial cells are oligodendrocytes and astrocytes Oligodendrocytes form the myelin sheaths that Wrap and insulate axons and they promote the saltatory conduction of electricsignals Astrocytes contribute to the structural integrity of the brain prOVide metabolic support to neurons maintain water and ionic balance and modulate synaptic transmission originating from the same progenitors are also produced in a particular sequence suggesting that the mechanisms controlling the specification of cell fates and the tirnin of progenitor division arrest and differentiation are also coordinated Temple 20 wt efforts have been made in the last 15 ym to elucidate the genetic programmes underlying the generation of cell diversity in the nervous system and transcription factors have been shown to play a central role in this process Initially different transcription factor families were thought to control particular steps in the differentiation of progenitor cells into neurons or glia but their unction turned out later to be broader and more complex Thus homeodomain proteins HD such as paired box 6 Pax6 and orthodenticle homolog 2 OtxZ were first shown to pattern the neural prirnordium whereas basic helixloophelix bHLH proteins such as achaetescute complex homologlike l Ascll also known as Mashl and neurogenin 2 NeurogZ also known as NgnZ were initially shown to promote the cell cycle arrest and neuronal differentiation of progenitors Additional functions of these transcription factor families have emerged more recently in particular in the generation of a diverse array of neurons and glia Recent evidence moreover suggests that generation of cell diversity in the nervous system involves extensive interactions between transcription factors of the HD and bHLH farni ies The purpose of this review is to provide an update on how the differentiation of neural progenitor cells into different classes of neurons and glia is coordinately regulated by different families of 3772 REVIEW Development 134 21 A Early development Late development Dorsal Pax6 0 Ngn12 Mash1 39 3 O 2 Mash1 0 Pax6 quot p 39p X M0 12 a 4r 1 VOVVZ interneurori Oiigz 0quot jg Mash1 pMN Motori ieuroi i ka22 quot P3 a V3 ii ileri ieuroi i Ventral Key B O Uncommmed progenitor Neuron Q Neuronal progenitor oligodendrocyleprogenilor Ol39QOdendTOCY Q Aslrocyleprogenilor Aslrocyle Fig 1 Sequential generation of different classes of neurons and glia in different domains of the ventral spinal cord A Progenitor domains in the ventral part of the mouse embryonic spinal cord The vertical aXis represents the dorsoventral aXis of the spinal cord the horizontal aXis represents developmental time B A crossesection ota mouse embryonic spinal cord dorsal top indicating the position of the progenitor domains shown in A Progenitor domains shown in A and B are pOepZ which generate sequentially VOPVZ interneurons oligodendrocytes and astrocytes pMN which generates sequentially motor neurons MNs oligodendrocytes and astrocytes p3 which generates V3 interneurons oligodendrocytes and astrocytes in the ventral spinal cord oligodendrocyte progenitors orange are generated from the pllll and p3 domains and also from the p0 and p1 domains Fogarty et al 2005 Patterning proteins see Box 2 including the homeodomain HD proteins Pax6 and kaZZ and the basic helixeloopehelixbHLH protein OligZ which establish the progenitor domains are initially coexpressed With the inhibitory HLl l proteins id and Hes in uncommitted progenitor cells grey The induction of the proneural proteins NgnZ and llash1 in progenitors promotes neurogenesis blue Whereas the induction of llas 1the maintenance ot OligZ and Nlltgtlt22 and the downregulation of Pax6 om oligodendrogenesis orange and the downregulation of patterning proteins and the maintenance of inhibitory HLH proteins promote astrogenesis pink pD progenitor domain for dorsal neurons See text and Sugimori et al Sugimori et al 2007 torturther details Development 134 21 REVIEW 3773 Box 2 Different classes of transcription factors specify neural cell fates The drfferentratron of neural stem cells lnto specrflc classes of neurons and glra rnvolves dlfferent categorres of transcrrptron factorsthat act at dlfferent stages and have drfferent functrons Patterning proteins these transcrlptron factors act early rn neural development by subdrvrdrng the neural prrmordrum rnto drstrnct domarns and by provrdrng progenrtor cells rn these domarns Wrth drstrnct posrtronal rdentrtres The homeodomarn HD factors of the Pax Nlltx and lrx famrlres and the basrc helrxeloopehelrx bHLH protern Olng provrde posrtronal rdentrty along the orsoventral axrs of the neural tube Patternrng proterns that provrde posrtronal rdentrty along the anteroposterror axrs rnclude HD proterns of the Otx Gbx En and Hox famrlres Progenitor proteins these are fate determlnants that are expressed rn drvrdrng neural progenrtors rncludrng patternrng proterns and other factors expressed later rn progenltor cells They control varlous aspects of a cell s fate such as rts neurotransmrssron type or axon path and rnclude LlMeHD proterns such as th3 Proneural proteins these transcrrptlon factors of the bHLH famrly rnrtrate programmes of neurogenesrs rn neural progenrtors Therr expressron leads to neuronal commrtment cell cycle exrt and drfferentratron and to Notch srgnallrng actrvatron rn adjacent progenrtors The marn mouse proneural proterns are llash1 Ascll neurogenrnllgnNeurog1e3 and Mathl Atohl Neuronal differentiation bHLH proteins these rnclude factors such as NeurolVl Neurod4 and NeuroD Neurod1that are rnduced by proneural protelns rn postmrtotrc cells and contrrbute to the neuronal drfferentratron programme Neuronal HD proteins these rnclude proterns such as Hb9llnx1 Mbhl BarhlZ and Brn3 Pou4f1 that are only expressed rn neural cells as the become postmrtotlc They contrrbute to the subtype specrfrc drfferentratron programmes that are actrvated rn postmrtotrc neuronal precursors Inhibitory HLH proteins the HLH ld proterns and the bHLH Hes proterns have antreneurogenrc and antreolrgodendrogenlc actlvlty and act by lnhrbltrng proneural bHLH proterns ld and Hes proterns and Olng ld proterns and by repressrng proneural gene expressron Hes proterns transcription factors see Box 2 The first part of the review discusses the role of progenitor proteins in regulating both the positional identity of progenitors and their fate The second part discusses the role of another group of transcription factors the proneural proteins in regulating both the fate of progenitors and their differentiation Finally in the third part I discuss the evidence that progenitor proteins and proneural proteins interact to specify cell fates and that interactions between transcription factors of the HD and bHLH amilies in particular play a major role in determining where and when different classes of neurons and glia are produced during development The review mostly focuses on mouse and chick in which most of the information on the role of transcription factors in speci cation of neural cell fates has been obtained Coupling spatial patterning and fate specification Soon after neural induction neural cells acquire distinct characteristics and different fates depending on their positions along the anteroposterior AF or rostrocaudal RC and dorsoventral DV axes of the neural tube This reflects the expression of different combinations of transcription factors that confer their positional identities on progenitors These transcription factors also promote the generation of different cell types at different positions and thus link the early step of neural tube patterning with the subsequent speci cation of different cell fates A number of progenitor proteins have been shown to subdivide the neural tube into distinct DV domains in which neural cells have distinct identities and fates Jessell 2000 Among the beststudied are the HD proteins Pax6 and Nk2 homeobox 2 ka22 also known as ka2 2 and the bHLH protein oligodendrocyte transcription factor 2 Olig2 ka22 establishes the ventralmost progenitor cell domain in the spinal cord called p3 which generates both neurons of the V3 interneuron class and oligodendrocytes see Fig 1 Olig2 is required for the generation of the pMN progenitor domain which is situated just dorsal to p3 and generates sequentially neurons of the motor neuron class and oligodendrocytes whereas Pax6 is involved in the establishment of the progenitor domains dorsal to pMN called p0p2 that produce different classes of interneurons followed by oligodendrocytes and astrocytes Fig 1 Besides the establishment of progenitor cell domains these patterning proteins Box 2 also play a later role in the selection of the cell types produced by these progenitors Hence Pax6 expression in mouse spinal cord or forebrain progenitors induces e formation of neurons whereas loss of Pax6 results in reduced neurogenesis and in precocious formation of oligodendrocyte and astrocyte precursors Hack et al 2005 Heins et al 2002 Sugimori et al 2007 Loss of Olig2 in the mouse spinal cord results in the absence of both motor neurons and oligodendrocytes and overexpression experiments in chick embryos and in progenitor cultures have shown that Olig2 can promote either neurogenesis or oligodendrogenesis depending on the developmental stage and the expression of other factors by progenitors Mizuguchi et al 2001 Sugimori et al 2007 Sun T et al 1 Zhou and Anderson 2002 Fig 1 and see below Thus patterning proteins are also involved in the generation of progeny from multipotent progenitor cells that have a restricted neuronal astroglial or oligodendroglial fate Different classes of neurons are produced by progenitors in nch domain of the neural primordium and the choice of neuronal subtype often also involves patterning proteins In the ventral spinal cord Olig2 is involved in the speci cation of motor neuron identity as shown by Olig2 misexpression in the chick neural tube which results in the generation of motor neurons at ectopic positions Mizuguchi et al 2001 Novitch et al 2001 Another striking example of a patterning transcription factor that controls sequential steps in neural development is Otx2 a HD protein that plays a central role in the initial speci cation of the anterior neural primordium and in its subsequent regionalisation into forebrain and midbra 3774 REVIEW Development 134 21 expression of a large number of transcription factors that control particular aspects of a cell s identity including other progenitor proteins proneural bHLH proteins and neuronal HD proteins see Boxes 1 d Hence Olig2 controls the motor neuron fate through the inhibition of ka22 and through the activation of transcription factors that are involved in motor neuron specification including the progenitor protein LIM homeobox protein 3 Lim3 also known as th3 the proneural factor Ngn2 and the neuronal HD protein motor neuron and pancreas homeobox l Mnxl also known as Hb9 Lee et al 2005 Novitch et al 2001 Otx2 also regulates both proneural proteins such as atonal homolog l Atohl or Mathl in the midbrain and Mashl in the thalamus and neuronal HD proteins such as Liml in the thalamus and conerod homeobox Crx in the retina Nishida et al 2003 Puelles et al 2006 Vemay et al 2005 Fig2 Distinct and overlapping functions of A homeodomain proteins and bHLH proteins in neural development A Different families o transcription factors are expressed during sequential phases of neural development The functions of patterning proteins thus vary in different parts of the nervous system and at different times A better understanding of these functions Will require the systematic characterisation of their transcriptional targets and the elucidation of t e mechanisms that determine the stage and cell typespecific expression of these targets Coupling fate specification and differentiation Once a progenitor cell has acquired a particular neuronal or glial identity the next step in the development of the cell lineage involves the arrest of cell divisions in the case of most neurons but not glial cells and the initiation of a programme of terminal differentiation Fig 2A Different classes of transcription factors coordinate y regulate cell fate specification and differentiation in neuronal an glial lineages Neural development Cell cycle exit Spatial Cell type Subtype Terminal patterning selection specification differentiation Patterning proteins are expressed early in neural development Pax6 ist en downregulated when progenitor cells become postmitotic Olig2 expression is maintained in oligodendrocyte progenitors but is downregulated in postmitotic neurons thinner bar while Nlltx22 expression is maintained in both neurons and oligodendrocyte progenitors Progenitor proteins such as th3 are induced in mitotic progenitors after the onset of patterning protein expression and remain expressed in postmitotic neurons Proneural protein expression is induced in subsets of progenitor cells after spatial patterning Progenitors that express proneural proteins undergo cell type selection and initiate neuronal subtype specification rapidly followed by cell B cycle exit Proneural protein expression is then sWitched off in most newborn neurons llash1 expression is maintained transiently in oligodendrocyte progenitors represented by a thinner bar Neuronal protein expression is induced in progenitor cells folloWing their cell cycle exit B The differentiation of multipotent progenitor cells into specific classes o postmitotic neurons and glia involves transcriptional cascades in which patterning proteins induce proneural proteins which in turn C induce often directly neuronal homeodomain proteins thin arrows These factors regulate different phases of neural development thicllt arrows see text Subtype specification is a initiated in diViding progenitors coordinately by progenitor proteins and proneural proteins and further promoted by neuronal proteins after cell cycle exit C The molecular mechanisms that underlie the synergistic actiVity o patterningprogenitor proteins and proneural proteins are largely un nown and could include a indirect interactions through regulation of distinct target genes eg Olig2 and Ngn2 llizuguchi et al 2001 NoVitch et al 2001 c b binding to distinct sites in the promoter of a no U Olig2 Patterning Patterning proteins Oligodendrocytes ka2 2 Progenitor proteins th3 Proneural proteins gm 73 Mashi Mathi Neuronal proteins Dlxi 2 L Mbhl Oligodendrocytes HbQ Cell type selection 8 Cell cycle exit Subtype Differentiation ubtype specification specification Transcription Transcription Transcription Transcription common target gene and synergistically activating target gene transcription eg lsll th3 Ngn2 and NeuroM Neurod4 Lee and Pfaf f 2003 c Cooperative binding of the progenitor protein and the proneural protein to adiacent sites in the promoter of a common target eg Mashl and Brn2 also known as Pou3f2 Castro et al 2006 White boxes represent transcription factor binding sites Development 134 21 REVIEW 3775 Neurogenesis proneural factors integrate spatial and temporal cues Transcription factors of the bHLH family play a central role in the differentiation of neural progenitors into neurons The expression of proneural bHLH proteins see Box 2 which in the mouse include Mashl Ngn13 and Mathl is both necessary and sufficient to promote the generation of differentiated neurons from undifferentiated progenitor cells reviewed by Bertrand et al 2002 Ross et al 2003 Proneural proteins control the commitment of multipotent progenitors to a neuronal fate Nieto et al 2001 Sun Y et al 2001 Tomita et al 2000 but also in uence the particular neuronal subtypes produced in a regionspecific manner reviewed by Bertrand et al 2002 Brunet and Ghysen 1999 Thus the expression of Mashl or N gn2 in forebrain progenitor cells promotes the generation of GABAergic and glutamatergic neurons respectively Berninger et al 2007 Parras et al 2002 whereas expression of Ngn2 in spinal cord progenitors is required for motor neuron identity Lee and Pfaff 2003 Mizuguchi et al 2001 Novitch et al 2001 Scardigli et al 2003 Proneural genes also control later aspects of the neurogenic process including t e arrest al 2000 Mizuguchi et al 200139 2004 as well as the subsequent migration of newborn neurons out of the progenitor zone of the neural tube and their terminal differentiation Beminger et al 2007 Hand et al 2005 Nakada et al 2004 Seibt et al 2003 This central role of proneural proteins in neuro genesis is likely to reflect the regulation of numerous genes that control the different steps in this process Fig 3 In order to promote neurogenesis proneural proteins must first inhibit the expression of the SoxB1 genes Soxl S0x2 and S0163 which promote the selfrenewal and Neural development multipotency of neural progenitors and also block their activity ough the activation ofan antagonistic Sox gene S0x21 Bylund et al 2003 Sandberg et al 2005 The exact mechanism by which proneural proteins commit progenitors to a neuronal fate is not known However by analogy with other developmental systems in which mechanisms of cell fate speci cation have been analysed in depth such as specification of the endomesoderm in sea urchin embryos or DV patternng in Drosophila embryos Levine and Davidson 2005 this step is likely to involve the activation of numerous downstream transcription factors the expression of which is stabilised through the formation of a regulatory network which in turn promotes the differentiation of committed neuronal progenitors Support for this model comes from studies in the developing retina cerebral cortex and spinal cord where Ngn2 regulates the expression of multiple genes that encode transcription factors of the bHLH Tbox and Sox families which have been implicated in neuronal differentiation Bergsland et al 2006 Kanekar et al 1997 MatterSadzinski et al 2005 Schuurmans et al 2004 Fig 3 The neuronal commitment of multipotent progenitors brought about by proneural proteins also involves the inhibition of astrocyte differentiation by distinct mechanisms including the sequestration of a gliogenic transcriptional complex away from glial promoters and inhibition of the expression of components of the gliogenic JAKSTAT signalling pathway He et al 2005 Sun Y et al 2001 The specification of neuronal identities by proneural proteins involves the regulation of neuronal HD proteins Box 2 Fig 1 and Fig 2B These factors have diverse roles in the specification of neuronal identities and their mutation result in a range 0 phenotypes A mutation in even skipped homeotic gene 1 vaI l l l p2 NeuroD1 80x4 Dcx Fbxw7 Tbr2 80x11 p35 SoxB1 I Sox21 FringeDellaSerrale SMADSTAT Hbg D39xwa Mbhl Dcamk Moior Telericephlic Spinai 09 neurons GABAergi commissural cells neurons neurons Notch signaling Selfrrenewal Inhibition Cell cycle Neuronal Neuronal Pluripolency of differentiation Aslrogliogenesis Neuronal subtype specification a rest differentiation migration Fig 3 Proneural proteins control multiple cellular processes and activate multiple target genes during neurogenesis Proneural proteins control many aspects of neurogenesis and some of their targets have been identified A Proneural proteins suppress the neural stem cell programme by interfering With the actiVity of 50x81 genes see text they select neuronal progenitors by directly activating Notch ligands and suppress astrogenesis by interfering With SMAD and STAT signalling see text B Different proneural proteins specify different neuronal subtype identities by directly activating l lD proteineencoding genes such as Hb9 Lee and Pfaff 2003 Dle2 Poitras et al 2007 and Mbhi also known as Barhl2 Saba et al 2005 C Proneural proteins also induce the expression of transcription factors that promote neuronal differentiation including bHLH proteins Tebox proteins an Sox proteins see text in addition to regulating transcription factors involved in cell fate specification proneural proteins also regulate genes that control later steps in the neurogenic programme such as cell cycle arrest neuronal differentiation and migration Farah et al 2000 Castro et al 2006 Ge et al 2006 Some of these genes eg Fbxw7 and doublecortinelike lltinase are regulated cooperatively by the proneural protein llash1 and the POL HD proteins Brnl also known as Pou3f3 and Brn2 Castro et al 2006 Ter Eomes Dcamlltl1 Dclkl 3776 REVIEW Development 134 21 leads to a complete switch in identity of V0 intemeurons into V1 intemeurons MoranRivard et al 2001 whereas mutations in distalless homeobox 1 and 2 DlxI and Dle two genes directly induced by Mashl results in ablock in the differentiation of striatal neurons Anderson et al 1997 Yun et al 2002 Poitras et al 2007 Mice mutant for HbQ a direct target of Ngn2 present a more subtle axon pathfinding defect in motor neurons Arber et al 1999 Lee and Pfaff 2001 Thaler et a1 1999 lmportantly the same proneural proteins specify different types of neurons in different regions of the nervous system For example Ngn2 promotes the generation of motor neurons in the ventral spinal cord and that of cortical pyramidal neurons in the dorsal telencephalon Parras et al 2002 Lee and Pfaff 2003 Schuurmans et al 2004 This re ects the regulation by proneural proteins of different sets of target genes in different regions possibly owing to the differential expression of interacting transcription factors see Lee and Pfaff 2003 Proneural proteins also influence the fate of progenitor cells indirectly by determining the timing of their last division Different classes of neurons are produced at different times in all regions of the developing nervous system This is in part owing to temporal changes in the composition of the signalling environment that directs the fate of progenitor cells Cepko et al 1996 Edlund and J essell 1999 McConnell 1995 Ohnuma and Harris 2003 Sockanathan and Jessell 1998 By controlling the timing of cell cycle exit proneural proteins determine the nature of the inductive signals that progenitors are exposed to at the time their fate is fixed ie during their nal division This role in controlling the birth date of neurons re ects two particular properties of proneural proteinsi First these factors have a unique role in promoting cell cycle exit an activity that is not shared by progenitor proteins such as Olig2 or Pax6 Second proneural proteins are only transiently expressed by neural progenitors around the time of their final division eg Britz et a1 2006 Miyata et al 2004 in contrast to patterning proteins which are expressed more uniformly by progenitor cells Fig 2A Whereas the spatial pattern of proneural gene expression is likely to be controlled by patterning proteins eg Scardigli et al 2003 Zhou and Anderson 2002 see Fig 2B and by crossrepressionbetween proneural genes Fode et al 2000 Gowan et al 2001 their timing of expression is controlled by extrinsic signalling pathways that regulate the differentiation of progenitor cells either positively eg Wnt signalling Hirabayashi et al 2004 or negatively eg Notch signalling Kageyama et al 2005 Thus proneural factors integrate spatial and temporal cues received from patterning proteins and from neurogenic and antineurogenic signals respectively They convert this information into neuronal subtypespecific differentiation programmes by activating neuronal HD determinants and by selecting the timing of progenitor cell division arrest Gliogenesis choosing between astroglial and oligodendroglial fates The sequential generation of neurons and glia is a general feature of the developing nervous system in vertebrates This neuronto glia switch is controlled by multiple mechanisms which include extrinsic signals transcription factors and modifications of histones and DNA reviewed by Rowitch 2004 Guillemot 2007 Miller and Gauthier 2007 At the transcriptional level a key step in the switch of neural progenitors to gliogenesis is the induction of Sox9 and NFIA two proteins that promote both astroglial and oligodendroglial fates These factors also inhibit neurogenesis and thus contribute to coordinating the onset of gliogenesis with the arrest of neurogenesis The gliogenic function of the HMGbox transcription factor Sox9 was revealed by analyzing Sox9null mice which produce fewer oligodendrocyte precursors and astrocytes and show a transient increase in motor neuron numbers in the ventral spinal cord Stolt et al 2003 Sox9 is subsequently expressed in oligodendrocyte precursors along with the related proteins Sox8 and 80x10 and the three factors play redundant functions in oligodendrocyte differentiation Wegner and Stolt 2005 The gliogenic activity of the CCAAT box elementbinding transcription factor NFlA has been demonstrated by silencing the N a gene in the chick spinal cord which prevents the generation of both astrocyte and oligodendrocyte precursors and leads to J quot 39 39 Converselv 39 A 39 N a in the chick spinal cord leads to precocious expression of glial markers in the ventricular zone and to theprecocious and excessive emigration of astrocyte precursors NFIA and NFIB are subsequently required for terminal astrocyte differentiation Deneen et al 2006 Sox9 and NFIA therefore have a common role in the specification of both oligodendroglial and astroglial progenitors but the two factors later have divergent functions in the v 39 anrl a trm vte respectively The nature of the mechanisms that underlie the activity of these two gliogenic factors and whether they act independently or in the same pathway are not known The choice between the alternative astroglial and oligodendroglial fates is controlled by different transcription factors reviewed by Rowitch 2004 The progenitor proteins Olig2 and ka22 which specify progenitor identities and neuronal fates in the ventral spinal cord see above later promote v I I 39 and inhibit 39 in r 39 domains Olig2 is required to generate oligodendrocyte precursors and to inhibit ectopic astrocyteproduction in the mouse spinal cord whereas coexpression of Olig2 and ka22 in the chick spinal cord is sufficient to induce oligodendrocyte precursors at ectopic locations Lu et al 2002 Zhou and Anderson 2002 Zhou et al 2001 The proneural protein Mashl an essential regulator of neurogenesis in many parts of the nervous system is also involved in the specification of a subset of oligodendrocyte precursors in the spinal cord and forebrain Parras et al 2004 Parras et al 2007 Sugimori et al 2007 There is therefore a striking convergence between the transcriptional programme that controls quot 39 and 39 39 Lutheventral neural tube Olig2 ka22 and Mash1 remain expressed in oligodendrocyte precursors and control their differentiation into myelinated oligodendrocytes suggesting that the same transcriptional mechanisms underlie cell type commitment and terminal differentiation in the oligodendroglial lineage Liu et al 2007 Qi et al 2001 M Nakafuku personal communication The bHLH protein SCL also known as Tall which is expressed in a restricted domain of the ventral spinal cord has the opposite role of promoting astrogenesis by inducing astrocyte precursorspecific genes and inhibiting oligodendrogenesis via repression of Olig2 Muroyama et al 2005 Other transcription factors known to promote astrocyte development act downstream of gliogenic signalling pathways such as STATS SMADs and RBPJk also known as Rbpj which are activated by the cytokineJAK BMP and Notch pathways respectively reviewed by Guillemot 2007 Miller and Gauthier 2007 However these factors have been shown to regulate the expression of late astrocytic differentiation markers such as glial fibrillary acid protein Gfap and it is unclear whether they also act in the specification of the astrocytic fate perhaps in combination with other factors such as NFIA or only in terminal astrocyte differentiation Miller and Gauthier 2007 Development l 34 Zl It is cleat om the foregoing discussion that many transcription factots involved in cell fate speci cation in the netvous system i a patticulat class ofneutons oi glia at a given time and location In the next section I discuss recent evidence that transcription factots indeed act in combinations in patticulat fot the L cotd and fot iiht ne of the tetina Transcrip ion factor codes specifying cell fates Specifying primary neural fates The idea that diffetent combinations of patterning ptoteins and iicuia f put forward by David Anderson and colleagues to explain theit nding that OligZ mutant mice lack both oligodendtocytes and Anrlm n 2002 Th y Wheteby 39rl u 39I a r i anngn 39Ngn2 y an intemeuton fate Following the dowmegulation of Ngn2 alone in the pMN domain would lead to the genetation of u u u i i u REVIEW 3777 m del was tecently extended and updated by Sugimoti et al Sugimoti et al 2007 to include othet patterning and ptoneutal ptoteins as well as inhibitory HLH factots see Box 2 that ate p quot 39 ventral spinal cotd To ditectly test the hypothesis that patterning ptoneutal and inhibitoty HLH ptoteins act nmhinatmiall 39 39 cell types ptoduced Sugimoti et al 2007 These expetiments u a mug Hes and Id Fig 4 For example wheteas exptession of Mashl u Mn m an a a a a Also wheteas exptession ofIdl ot Hesl alone in neutal stem cell any ii u in may quot 39 Mmquot et al 2007 For example the beginning and end ofthe neutogenic 7 and Oli 2 39 39 39 by the onset and termination of neutogenin ptotein exptession u u am domain coincides with the onset of Mashl exptession and the i A 2002 see also Novitch et al 2001 Mizuguchi et al 2001 This ptogenitots Fig l Fig 4 The combinatorial activity of Ngn13 Ma5h1 He51lld1 patterning proteins and proneural N N N 7 proteins promotes neural cell typ commitment The compinatorial acllvllles of patterning proteins vertical axis an o O 0 Y 0 proneural proteins and in i itory HLH proteins norizontal axls int ent of A A Ak progeni r ells to neuronal N oligodendroglial 0 or astroglial A fates are shown as ntries n a matrlx These results N N N N s were 0 wed by compin tions of factors in neural stem cell Pax6 p Pax6 Pax6 population cultures d rive tom rat Paxe 0 0 U 0 0 empryonicspinal cord The errect or particular Neill2 Mashl Heslldl transcription factor combinations on ne A 7 0 generation oftl39ie primary neural cell types is represented p 3939 for significant induqion 39 for significant represslon an 39 39 orno N N o N o N e a lvlly See text and Sugimori et al Sugimori Ohgz Ohgz Ohgz et al 2007 for details Oligz i3 Y my 0 0 Y 0 Ngnz Mashl Heslldl A o A A e A o N 7 N N N e NW2 2 NW2 2 ka22 0Y 5 o if 0 0 None Mashl Heslldl A o A o A 0 3778 REVIEW Development 134 21 The study by Sugimori et al Sugimori et al 2007 thus provides evidence that cooperation between patterning proneural and inhibitory HLH proteins establishes a molecular code that determines both the spatial and the temporal patterns of neurogenesis and gliogenesis Proneural proteins determine the timing of the neurontoglia switch as shown by the analysis of various mutant mice Sugimori et al 2007 as well as the rate of cell cycle exit and differentiation see above and thus control the numbers of neurons and glial cells produced by each progenitor domain Patterning proteins also contribute to the timing of the generation of the different neuronal and glial populations and their in size by attenuating the neurogenic activity of Ngn2 by modulating the neurogenic and oligodendrogenic activities of Mashl and by suppressing the astrogenic activity of the Hes and Id proteins Sugimori et al 2007 Moreover patterning proteins determine the spatial patterns of neurogenesis and gliogenesis by establishing distinct profiles of proneural gene expression in different progenitor domains Scardigli et al 2003 Zhou and Anderson 2002 and by modulating the neurogenic or gliogenic activity of proneural proteins in wch domain Sugimori et al 2007 Other factors are likely to be involved as well such as the Dlxl and Dlx2 proteins which promote neurogenesis and inhibit oligodendrogenesis via repression of Olig2 in progenitors of the mouse forebrain Petryniac et al 2007 Specifying neuronal subtypes Synergies between progenitor proteins mostly of the HD family and bHLH proteins have also been implicated in the specification of neuronal subtype identities in different model systems particularly in the mouse and Xenopus retina see Hatakeyama and Kageyama 2004 Wang and Harris 2005 Multiple bHLH proteins are expressed in dividing retinal progenitor cells and some of them are maintained in particular retinal neuron populations Thus both Mashl and another bHLH protein Math3 also known as Neurod4 are expressed transiently by differentiating bipolar cells implicating these factors in the specification of this neuronal subtype There is indeed a reduction lVlalliS Ganglion Amacrlne Horizontal in the number of bipolar cells in Mash singlemutant mouse embryos and an almost complete loss in Mash Math3 double mutant embryos with a compensatory increase in the number of Miiller glial cells Tomita et al 2000 However misexpression of Mashl or Math3 in retinal progenitors results in the production of photoreceptors at the expense of Miiller glial cells suggesting that these bHLH proteins are not sufficient to specify bipolar cells Hatakeyama et al 2001 The HD protein ChxlO also known as st2 is also expressed in bipolar cells and a mutation in mouse CthO results in a complete loss of these neurons Hatakeyama d Kageyama 2004 However misexpression of ChxlO produces Miiller glial cells or undifferentiated cells in the inner nuclear layer of the retina indicating again that Chx10 expression is not sufficient to promote the bipolar cell identity By contrast misexpression of Chx10 together with Mashl or Math3 promotes the generation of bipolar cells Hatakeyama et al 2001 Thus the bHLH proteins Mashl and Math3 alone can promote neurogenesis but they must interact with the HD protein ChxlO to specify the particular bipolar subtype Reciprocally ChxlO alone provides retinal cells with a laminar inner nuclear layer identity but it must act with Mashl or Math3 to specify a particular neuronal subtype Lossoffunction and misexpression studies in mouse with other transcription factors expressed by subsets of retinal neurons lead Ryoichiro Kageyama and colleagues to propose a generalisation of this model in which a transcription factor code that involves combinations of bHLH and HD proteins controls the specification of the different classes of retinal cells Hatakeyama and Kageyama 2004 Fig 5 In this model HD proteins determine the laminar position of retinal cells whereas bHLH proteins determine their time of birth which is tightly correlated with the identity of the cells produced Cepko et al 1996 bHLH proteins may thus contribute to cell fate specification by determining the precise timing of cell cycle exit of retinal progenitors Ohnuma and Harris 2003 as well as by directly activating the expression of cell fate determinants as discussed above in the context of the spinal cord Gangllon cell layer lvlaslll lvlalh inner nuclearlayer Muller glla Outer nuclear layer Fig 5 Model of neuronal subtype specification in the retina by combinations of HD and bHLH proteins Dl erent comblnatlons ot bHLH protelns purple and HD protelns red are expressed by the dl erent Classes of neurons and glla ln tne retlna From mouse mutant analyses and trom coexpresslon of HD protelns and bHLH protelns ln mouse retlnal explants Hatallteyama and Kageyama have proposed that the comblnatorlal aCthlty ot dl erent HD and bHLH protelns determlnes tne tate ot retlnal cells See text and Hatallteyama and Kageyama Hatakeyama and Kageyama 2004 tor detalls NeuroD Neurodl Development 134 21 REVIEW 3779 Conclusion This review has focused on a few wellstudied examples and one must as in neural cell ate specification The fact that such interactions have been implicated in the selection of the primary neural fates and in the specification of neuronal phenotypes in regions as diverse as the spinal cord the retina and the forebrain suggests that this is a fundamental mechanism that operates throughout the nervous system although this remains to be established T 39 erquot t J of HD and bHLH proteins in the different systems discussed above remain largely unknown Fig 2C An attractive model is that these factors cooperate to regulate common target genes that are themselves involved in fate specification In one of the few examples that have been well documented the cooperation of Ngn2 with the LIMHD proteins th3 and Isll to specify motor neurons involves the synergistic activation by these factors of the Hb9 gene Lee and Pfaff 2003 There are other examples in the nervous system and in other tissues of bHLH proteins and HD proteins that regulate gene x ression through cooperative DNA binding transcriptional activation involvin in some cases p ys1ca interactions between members of these two families Ohneda et al 2000 Poulin et al 2000 Sun et al 2003 Berkes et al 2004 Castro et al 2006 qlllll ldl 39 nil in operate for A T 39 of neural cell fates Current efforts to characterise the molecular pathways controlled by transcription factors in the developing nervous system will eventually elucidate the mechanisms that underlie their combinatorial activities including the synergistic regulation of common target genes and perhaps also less direct mechanisms Ten years after David Anderson and Yuh Nung Jan discussed the respective contributions of bHLH proteins and HD proteins in the determination of the neuronal phenotype Anderson and Jan 1997 one can appreciate how much has been learned in the interval about the functions of individual transcription factors but also how much remains to be lmt about how they perform these functions Many thanks to Dawn Butier for drawmg thefigures and to Sieeran Ang Meianie Lebei Masato Nakafu u or space iimitations Researc in my Taboratory is supported y grants ro e European Commission and the WeHcome Trust and by institutionai funds from the Medicai Research Councii 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