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Climbing fiber development: do neurotrophins have a part to play

The climbing fiber input to the cerebellum is crucial for its normal function but those factors which control the development of this precisely organized pathway are not fully elucidated. The neurotrophins are a family of peptides, which have many
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  Climbing ber development: do neurotrophins have a part toplay? Rachel M Sherrard and Adrian J Bower Developmental Neuroplasticity Laboratory, School of Medicine, James Cook University, Queensland, Australia  The climbing ber input to the cerebellum is crucial for its normal function but those factors which control the devel-opment of this precisely organized pathway are not fully elucidated. The neurotrophins are a family of peptides, whichhave many roles during development of the nervous system, including the cerebellum. Since the cerebellum and infe-rior olive express neurotrophins and their receptors, we propose that neurotrophins are involved in the regulation of climbing ber development. Here we review the temporo-spatial expression of neurotrophins and their receptors atkey ages during climbing ber development and then examine evidence linking neurotrophins to climbing ber devel-opment, including some of the intracellular pathways involved. During prenatal development the expression of neu-rotrophins in the hindbrain coupled with their function in neurogenesis and migration, is consistent with a role of NT3in inferior olivary genesis. Subsequently, cerebellar expression of two neurotrophins, NT3 and NT4, is concurrent witholivary receptor expression and the time of olivary axonal outgrowth and this continues postnatally during early climb-ing ber synaptogenesis on Purkinje cells. The expression-pattern of neurotrophins changes with age, with fallingNGF, NT3 and NT4 but increasing granule cell BDNF. Importantly, olivary expression of neurotrophin receptors, andtherefore climbing ber responsiveness to neurotrophins, falls specically during maturation of the climbingber–Purkinje cell synapse. The function of BDNF is less certain, but experimental studies indicate that it has a rolein climbing ber innervation of Purkinje cells, particularly synaptogenesis and synaptic plasticity. Its importance ishighlighted by the overlap of BDNF signalling with several cellular pathways, which regulate climbing ber maturation.From the data presented, we propose not only that neurotrophins are involved in climbing ber development, but alsothat several act in a specic temporal order.  ½ The Cerebellum 2002; 1: pp 265–276   ½  265 Received 14 January 2002; revised 20 March 2002; accepted 20 March 2002  Correspondence:  Dr RM Sherrard, School of Medicine, James Cook University,Townsville, Queensland 4811, Australia. Fax: +61 7 47 81 69 86. Email:  © 2002 Martin Dunitz Ltd Keywords: cerebellum – climbing bers – development – growth factors – neurotrophins  Sherrard RM, Bower AJ. Climbing ber development: do neurotrophins have a part to play?Cerebellum 2002; 1: 265–276 Introduction The cerebellum is involved in motor learning andcontrol and the climbing ber input from the inferiorolive is essential for this function. 1 This pathway fromthe inferior olive to target Purkinje cells within the cere-bellar cortex has a highly specic organization, 2 whichdevelops in its basic format prenatally 3,4 but undergoesconsiderable postnatal renement to produce its nalprecise topography. Despite extensive investigation, themechanisms that control the development of thispathway remain unclear.Studies on the development of the olivocerebellarpathway have been reviewed elsewhere. 5 However whatfunction, if any, is played by the many growth factorslocalized within the developing nervous system 6 has notbeen examined. Of the many growth factors currentlyidentied in the immature nervous system, several havebeen located within the olivocerebellar system. 7–9 Of these, the neurotrophins have been most widely studiedand their role in cerebellar development has previouslybeen reviewed. 10 Since there is differential expression of neurotrophins within the developing cerebellum (forreview see ref. 10) and their receptors within the inferiorolive, 11–13 it may be proposed that these growth factorsare involved in climbing ber development. Unfortu-nately there are no studies which directly assess such arole. Therefore the purpose of this review is to discussthose recent data which provide, in the opinion of theauthors, evidence (albeit indirect) to suggest a signi-cant action for neurotrophins in the development of theolivocerebellar path. In order to address this there areseveral pieces of evidence to be considered:  the expression patterns of the neurotrophins and theirreceptors in the olivocerebellar system and how theyrelate to stages of climbing ber development,   data from transgenic and mutant animals, in whichneurotrophin or receptor expression is altered, thatindicate their effects on climbing ber development,  evidence from experimental manipulations to thispathway and the associated changes in either neuro-trophins or their receptors, which implicate neuro-trophin function in climbing ber development,  nally some of the intracellular mechanisms whichhave been demonstrated to control climbing bergrowth and maturation and their overlap with the sig-nalling systems of neurotrophins. Neurotrophins: an overview The neurotrophins are a family of peptides which shareconsiderable structural homology. 14 The family com-prises nerve growth factor (NGF), brain-derived neu-rotrophic factor (BDNF), neurotrophin 3 (NT3),neurotrophin 4/5 (NT4) and, in sh, neurotrophin 6and neurotrophin 7. 14 These peptides exert their effectsthrough transmembrane receptors, of which there are 2types: (1) the low afnity nerve growth factor receptor,p75, which binds all the neurotrophins with equal afn-ity, 15 and (2) specic high afnity trk receptors. 16 Thehigh afnity binding of each neurotrophin to its trkreceptor is specic, with NGF binding to trkA, BDNFand NT4 binding to trkB, and NT3 binding predomi-nantly to trkC, but also at high concentration to trks Aand B. 16 Neurotrophin binding to p75 modies ligandbinding to the high afnity trk receptor, aids retrogradetransport of ligand-receptor complexes to the cell somaand has a role in cell death. 17 In contrast, ligand bindingto the trk receptor activates intrinsic tyrosine kinaseactivity and thus intracellular signalling cascades 14 whichproduce the biological response to neurotrophins.Briey, these biological effects include neuronal sur-vival, differentiation, connectivity and synaptic plasticity(e.g. for a review see ref. 6). In order to produce thesemany functions, neurotrophins can act in two direc-tions; rstly as target-derived trophic agents interactingwith afferent axons 18 and/or secondly as afferent–deliv-ered molecules interacting with their target cells. 19 Neurotrophins: a role in climbing berdevelopment? Important for any proposed action of neurotrophins inclimbing ber development, is that they regulate neuronalfunctions which occur during olivocerebellar pathwaygrowth and maturation: axonal outgrowth, 20 dendriticremodelling 21 and renement of axonal arbours. 22 However, in order to exert such functions on the climbingbers, the neurotrophin and its relevant receptor have tobe located at the appropriate sites (see Table 1). Neurotrophin expression during climbing berdevelopment Climbing ber development occurs from the initial pro-duction of olivary neurons until the completion of climbing ber–Purkinje cell interactions. In the rat thisspans the time frame between olivary neurogenesis atembryonic day 13 (E13) 23 and the end of climbingber–Purkinje cell synaptogenesis at postnatal day15. 24,25 Prenatal development  (a) Early inferior olive genesis. Inferior olivary neuronsarise in the precerebellar neuroepithelium of the hind-brain on days E13–14. 23 During this period of neuro-genesis there are high levels of NT3 synthesized in theembryonic brain, 7 however this has not been furtherlocalized to the neuroepithelium of the hindbrain. NT3inuences neuronal generation from precursors 14 butwhether this includes olivary neurogenesis is not known. (b) Inferior olivary migration and axonogenesis. After theirgenesis immature olivary neurons migrate to their nalposition in the ventral medulla where they settle byE16–17 and reorganize into the adult multi-folded unitwith discrete subnuclei by E19. 26 As stated above thereis extensive NT3 synthesis in the embryonic brain. 7 Ithas been proposed that NT3 is involved in migration of pre-cerebellar neuroblasts away from the pre-cerebellarneuroepithelium 27 and it is highly likely that the neuronsof the inferior olive can be included in this process.During this period of migration between E13–16, theimmature olivary neurons commence their axonogene-sis. 26 At these ages the growing axon tips have crossedthe midline and extend towards their targets in the con-tralateral cerebellum where NT4 mRNA, a potent stim-ulator of axonal elongation in vitro, 28 is expressed at highlevels from E13 onwards. 29 While the cerebellar locationof NT4 synthesis has not been identied, at this earlyage the predominant cells of the cerebellar plate areneurons of the deep cerebellar nuclei and Purkinjecells, 23 both of which receive climbing ber afferents. 1 Furthermore neurotrophin receptors, particularly thelow afnity p75, are synthesized in the inferior olivefrom E16. 30 Since p75 is transported to axon termi-nals, 31 this indicates that these developing olivaryneurons are capable of responding to neurotrophinsbeing secreted by their targets cells in the cerebellaranlage 29 (Figure 1A). (c) Climbing bers reaching the cerebellum. Climbing beraxons rst enter the cerebellar anlage at E17 3 where theyare located supercially in the presumptive molecularlayer between the Purkinje cell plate 3,23 and the spread-ing external germinal layer (EGL). 23 Between E19–20these climbing ber axons enter the Purkinje cell plateto form loose plexuses around immature Purkinjeneurons. 3 266  ½ RM Sherrard, AJ Bower    Neurotrophins and climbing ber development   ½  267    T  a   b   l  e   1    A  s  u  m  m  a  r  y   t  a   b   l  e  o   f   t   h  e  n  e  u  r  o   t  r  o  p   h   i  n  a  n   d  n  e  u  r  o   t  r  o  p   h   i  n  r  e  c  e  p   t  o  r  e  x  p  r  e  s  s   i  o  n   i  n   t   h  e  o   l   i  v  o  c  e  r  e   b  e   l   l  a  r  s  y  s   t  e  m    d  u  r   i  n  g   d  e  v  e   l  o  p  m  e  n   t .   A   l  s  o  w   h  e  r  e  r  e   l  e  v  a  n   t ,   t   h  e  c  e   l   l  s  w   h   i  c   h  a  c  c  u  m  u   l  a   t  e  p  e  p   t   i   d  e .   F  o  r  a  c  o  m  p   l  e   t  e  r  e  v   i  e  w  o   f  n  e  u  r  o   t  r  o  p   h   i  n  s   i  n  c  e  r  e   b  e   l   l  a  r   d  e  v  e   l  o  p  m  e  n   t   t   h  e  r  e  a   d  e  r   i  s  r  e   f  e  r  r  e   d   t  o   L   i  n   d   h  o   l  m   e   t  a   l ,   1   9   9   7 .    1   0    T   h  e  s  u  p  e  r  s  c  r   i  p   t  n  u  m   b  e  r  s   i  n   d   i  c  a   t  e  r  e  p  r  e  s  e  n   t  a   t   i  v  e  r  e   f  e  r  e  n  c  e  s .    C   F   D  e  v   l   S   t  a  g  e   A  g  e   C  e  r  e   b  e   l   l  u  m   P  u  r   k   i  n   j  e  c  e   l   l   E   G   L   /   G  r  a  n  u   l  e  c  e   l   l   D   C   N   I  n   f  e  r   i  o  r   O   l   i  v  e    I   O   N  g  e  n  e  s   i  s   E   1   3 -   E   1   6   N   T   4  m   R   N   A   3  +    2   8   p   7   5   3  +    2   9    C   F  a  x  o  n  o  g  e  n  e  s   i  s   E   1   7 -   E   2   1   N   T   4  m   R   N   A   3  +    2   8    t  r   k   B –    3   1    N   T   3  m   R   N   A   3  +    3   1   p   7   5   3  +    2   9    *   t  r   k   B   &   C   2  +    3   1    E  a  r   l  y   t  r  a  n  s   i  e  n   t   P   0 -   P   5   N   G   F  m   R   N   A   2  +    3   6 ,   3   8   s  y  n  a  p   t  o  g  e  n  e  s   i  s   N   T   4  m   R   N   A  +    2   8 ,   3   5    t  r   k   C    3   1    N   T   3  m   R   N   A   3  +    7 ,   9 ,   3   5 ,   3   8    B   D   N   F  m   R   N   A   2  +    9 ,   3   1    t  r   k   A  +    1   2    t  r   k   B   &   C   3  +    1   1 ,   1   2   p   7   5   3  +    9 ,   2   9    N   T   3   3  +  p  e  p   t   i   d  e    4   0    N   T   4   B   D   N   F  +   / -   t  r   k   B   2  +    4   3    t  r   k   B   3  +    4   2 ,   4   4 ,   4   5    B   D   N   F  m   R   N   A   3  +    9    C   F  m  a   t  u  r  a   t   i  o  n   &   P   7 -   P   1   5          ¯    N   G   F  m   R   N   A   B   D   N   F  m   R   N   A  +   / -    3   5              B   D   N   F  m   R   N    7 ,   9 ,   3   5          ¯         ¯    t  r   k   B   &   C  +    1   2   s  y  n  a  p   t   i  c              N   T   4  m   R   N   A    3   5 ,   3   8    B   D   N   F          ¯    N   T   3  m   R   N   A    7 ,   9 ,   3   5          ¯         ¯   p   7   5  +    9 ,   2   9   s   t  a   b   i   l   i  z  a   t   i  o  n   N   T   4   2  +  p  e  p   t   i   d  e    4   0    N   G   F   t  r   k   B   2  +    4   3 ,   4   5    t  r   k   B   2  +    4   4 ,   4   5          ¯    B   D   N   F  m   R   N   A    9    *  =  p  r  o  p  o  s  e   d   l  o  c  a   t   i  o  n .   T  r   k   B  a  n   d   C  a  r  e   i  n   t   h  e   b  r  a   i  n  s   t  e  m ,   t   h  e   i  n   f  e  r   i  o  r  o   l   i  v  e   p  e  r  s  e    h  a  s  n  o   t   b  e  e  n  e  x  a  m   i  n  e   d   (  s  e  e   t  e  x   t   ) .   3  +  =  v  e  r  y  s   t  r  o  n  g  e  x  p  r  e  s  s   i  o  n  ;   2  +  =  m  o   d  e  r  a   t  e  e  x  p  r  e  s  s   i  o  n  ;  +  =  w  e  a   k  e  x  p  r  e  s  s   i  o  n  ; -   =  n  e  g  a   t   i  v  e  At these ages from E16–21 there is concurrent expres-sion of neurotrophins at the site of the climbing berterminals in the cerebellar anlage and neurotrophinreceptors in the inferior olive. Although, as indicatedabove, Purkinje cell expression of neurotrophins at thisage has not been claried, NT4 mRNA is highlyexpressed in the cerebellar anlage. 29 In addition thedeveloping EGL expresses NT3 mRNA. 32 Both NT3and NT4 induce axonal growth 20,28 and NT4-trkB sig-nalling activates mitogen-activated protein kinase cas-cades 28,33 which modify neurolament 34 andmicrotubule 35 stability and therefore growth cone motil-ity and axonal elongation. At these ages the immatureinferior olive expresses the low afnity p75 receptor. 30 268  ½ RM Sherrard, AJ Bower  1A: E13–16ChAMidbrain4 th VDCNEGL:NT3Medulla:trks B and CION: p75,?trk1B: E22 5 P0MidbrainNT4DCNBDNF 4 th VEGL:NT3ION: p75,trks A, B and C Figure 1 A schematic diagram indicating site of neurotrophin and receptor syn-thesis during prenatal development and the direction of climbing bergrowth (long arrowed lines). For the sake of clarity the left olive hasbeen omitted. (A) E13–16. At these ages there is a rudimentary cere-bellar anlage (CbA) expressing NT4. p75 is synthesized in the inferiorolive and trks B and C are synthesized in the medulla. (B) E22 =Birth. At birth the EGL, Purkinje cell plate and deep nuclei arepresent. NT3, NT4 and BDNF are synthesized in the cerebellumwhile the receptors are located in the inferior olive. CbA = cerebellaranlage; DCN = deep cerebellar nuclear neurons; EGL = external ger-minal layer; ION = inferior olive; O = immature Purkinje cells; ® =direction of Purkinje cell migration; Þ = route of climbing ber axons Furthermore, high afnity trkB and C receptors arestrongly expressed in neurons of the developing brain-stem between E13–18 32 well in advance of their respec-tive ligands. Although not specically localized to theinferior olive embryonically, the inferior olive doesexpress both trkB and C at high levels soon afterwardsat birth (E22), 11,12 so it is likely that the expression inthe embryonic brainstem includes the inferior olive.Therefore the spatiotemporal congruity of neu-rotrophins in the cerebellar plate at the site of climbingber terminals with olivary receptor synthesis is entirelyconsistent with a target-derived trophic action of cere-bellar neurotrophins on olivary climbing ber axons 18 inducing their growth (Figure 1B). In summary, during prenatal development the expres-sion of neurotrophins in the hindbrain coupled withtheir function in neurogenesis and migration, is consis-tent with a role of NT3 in inferior olivary genesis. Sub-sequently two neurotrophins, NT3 and NT4, aresynthesized in the early cerebellar anlage at the time of olivary axonal outgrowth. This is concurrent witholivary expression of neurotrophin receptors indicating acapacity to respond to these neurotrophins. Sinceneurotrophins are known to promote axonal growthduring development, 20,28,33 it can be proposed that theypromote prenatal climbing ber axonal growth to thecerebellum. Postnatal climbing ber development  (a) Axonal growth and temporary synaptogenesis. By birth,climbing ber axons are already in the cerebellar corticalplate where they ramify in the Purkinje cell zone. 3 Atthis stage their morphology is not typical of climbingber arbours, 36 as many axons end in growth cones 37 with only a few immature synapses in the mostadvanced ventral lobules of the cerebellum. 37 Despitetheir presence, these immature climbing bers have notdeveloped functional synapses on Purkinje cells. 24 Between P3–5 the immature climbing bers branchextensively, 36 developing mature synapses on temporarydendrites and non-synaptic axosomatic contacts onPurkinje cells, 37 such that from P3 climbing bers canstimulate Purkinje cell activity. 24,25 By P5 the climbingbers form the classical “pericellular nest” being aroundand just below the Purkinje cell layer 36–38 and synapsingon Purkinje cell perisomatic processes. 23,37 Each Purk-inje cell receives several climbing bers 38 with a maximalinnervation of 3.5 climbing bers per Purkinje cell atP5. 24,25 However the actual bers have variable mor-phology with the axons terminals both adjacent to Purk-inje cells and in the inner granular layer (IGL). 36 Similar to the prenatal stages, early postnatal climbingber development correlates with the expression of neurotrophins and neurotrophin receptors in both thecerebellum and inferior olive. NGF, NT3, BDNF &NT4 are all synthesized in the cerebellum at P0. 39 WhileNGF mRNA is expressed in the cerebellum 39–42 its site  of synthesis has not been localized. Furthermore, levelsfall postnatally 39–42 and the olivary expression of trkAreceptors is consistently low. 12 This combination of apparently small quantities of trophin and receptorsdoes not suggest a major role for NGF in climbing bergrowth and synaptogenesis. In contrast, NT3 is stronglyexpressed, in the EGL, 7,9,39,42 but not apparently in theclimbing ber targets—the Purkinje cells. 9,39 BDNF isonly weakly synthesized in the cerebellum beforeP10 39,43 and is predominantly in the deep cerebellarnuclei. 9,32 As with prenatal development, NT4 continuesto be expressed in the cerebellum, but unfortunately thecells producing it have not been identied. 29,39 Thereforethere is a selection of neurotrophins synthesized withinthe developing cerebellum which may regulate climbingber development.In the inferior olive at these early ages to P5, there ishigh expression of p75 9,30 and high afnity trkB andC 11,12 receptors. In addition, there is extensive NT3 andNT4 protein in the inferior olive, 44 despite no demon-strable olivary synthesis 9 only cerebellar synthesis. 29,39 This is consistent with retrograde transport of neuro-trophins from the cerebellum to the olive via the climb-ing bers. Therefore, the temporospatial distribution of cerebellar neurotrophin synthesis, inferior olivary recep-tors and accumulation of NT3 and NT4 are indicativeof some interaction between neurotrophins of the cere-bellum and the olivary climbing bers. In the case of NT3, this would indicate paracrine support from eitherthe EGL or the few granule neurons via the IGL collat-erals. However, it cannot be presumed that these neu-rotrophins actually cause the climbing ber growth andsynaptogenesis. It is only possible to propose such afunction since neurotrophins have a recognized role inaxonal growth, 20 arborization and synaptogenesis. 45 In addition to retrograde action, neurotrophins arealso anterogradely transported. 19 At these ages of climb-ing ber growth and synaptogenesis, the inferior olivestrongly expresses BDNF mRNA 9,43 in the absence of extensive protein content. 44 Notably, there is an abun-dance of trkB in the cerebellum 46 including in Purkinjecells. 47–49 Therefore the inferior olive may deliver BDNFto the Purkinje cells via the climbing bers (Figure 2A).In addition, since the inferior olive also synthesizes trkBreceptors, it is possible that olivary BDNF may beacting in an autocrine fashion upon its own axon termi-nal. Such an action has been documented in corticalneurons and it results in active neuritic elongation andrearrangement. 21 (b) Maturation and collateral regression. From P7 to P15climbing bers mature. This involves translocation totheir permanent position on developing Purkinje cellapical dendrites and considerable axonal growth in par-allel with the increasing Purkinje cell dendritic tree, 23,36 while still maintaining the IGL terminals 36 that areretained to maturity. 50 At the same time extraneousclimbing ber collaterals withdraw so that Purkinje cell  Neurotrophins and climbing ber development   ½ 269 2A: P0–P5 EGL:NT3mRNA PCL:trkB B     B B B  B B   BBB    ?    N    T   3 ?    B    D    N    F     ION: p75,trkA, B and CBDNFmRNA,NT3 and NT4DCN:BDNFmRNANGF and NT4 ? site ?NT4 EGL: ¯ NT3mRNA ?BDNF IGL:BDNFmRNA     ¯ NGF,BDNF NT4 (peptides) ION: ¯¯ BDNFmRNAand receptors    B   B ?2B: P7–P15 Figure 2 A schematic diagram indicating site of neurotrophin and receptor syn-thesis during postnataldevelopment of climbing bers (long arrowedlines). (A) P0–P5. Climbing ber axons (arrowed lines) ramify aroundthe Purkinje cells and form synapses on perisomatic processes. Purk-inje cells express trkB receptors (-B). Since the inferior olive expressesboth trkB and C and accumulate NT3 and NT4, possible directionsof neurotrophin signalling are indicated (dotted arrows). (B) P7–P15.During climbing ber maturation olivary BDNF and receptor expres-sion falls. While BDNF from granule cells appears to stabilize parallelber–Purkinje cell synapses, 52 the interactions at the climbingber–Purkinje cells synapse when supernumerary collaterals regress(dotted line) remain uncertain. B = trkB receptor; DCN = deep cere-bellar nuclear neurons; EGL = external germinal layer; IGL = internalgranular layer; ION = inferior olive. innervation by multiple climbing bers regressesrapidly 24,25 to rene the climbing ber–Purkinje cellinteraction. During this period of synaptic stabilization and matu-ration, cerebellar neurotrophin synthesis is changingwith BDNF, NT3 and NT4 synthesis rising but NGFsynthesis falling. 39,42 There is extensive evidence linkingNT3 and BDNF to granule cell development (for areview see ref. 10) and granule cell–Purkinje cell matu-ration 51–53 and it cannot be re-addressed here. In con-trast the cells which synthesize NGF and NT4 have notbeen identied although both peptides have been local-ized in Purkinje cells. 40,44 Also neurotrophin synthesis byPurkinje cells remains unclear: they do not produceNT3, 9,39 only small amounts of BDNF mRNA havebeen identied in some cells 39 and their relation to theproduction of NGF and NT4 remains unknown. This isparticularly unfortunate since target Purkinje cells arecentral to the retrograde signalling controlling climbingber maturation and regression, 54 which excludes anydirect paracrine action of granule-cell-derived neuro-trophins on the climbing ber terminals during thisprocess of maturation. Furthermore, olivary synthesis of neurotrophin receptors, p75 9,30 and trks B and C, 11,12 falls between P7 and P15. This suggests decreasingolivary (and therefore presumably climbing ber axonterminal) responsiveness to neurotrophins. An inabilityto respond to neurotrophins is associated with decreased
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