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13 Cerebellar Neurogenesis
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13.3.1 Primary Cilia andGCP Proliferation
The primary cilium, a sensory cellular organelle mediating
chemo- and mechanotransduction, plays a central role in
GCP proliferation (Chizhikov et al. 2007; Spassky et al.
2008). Several signaling molecules are trafcked in the cil-
ium and its surroundings (May etal. 2005; Corbit etal. 2005;
Liu etal. 2005; Huangfu and Anderson 2005; Haycraft etal.
2005). The primary cilium is required for SHH signal trans-
duction, to promote expansion of the GCP pool (Chizhikov
et al. 2007) and the fact that mutations in genes encoding
components of the primary cilium cause Joubert and Meckel
syndrome, characterized by vermis hypoplasia or aplasia
(e.g., Valente etal. 2006). Proliferation and the response to
SHH are severely impaired in Joubert or Meckel syndrome
patients (Aguilar et al. 2012). More recently, ZNF423/
Zfp423, a gene implicated in rare cases of Joubert syndrome,
was found to be required for the response to SHH (Hong and
Hamilton 2016).
ATOH1 has been long known to positively regulate the
SHH transduction pathway but is also required for the maintenance of primary cilia, which keep GCPs competent to
respond to SHH (as mentioned, the loss of primary cilia
causes GCPs to exit their proliferative state). ATOH1 activates ciliogenesis by transcriptionally regulating Cep131,
whose gene product facilitates the clustering of centriolar
satellites at the basal body. Importantly, ectopic expression
of Cep131 counteracts the effects of Atoh1 loss in GCPs by
restoring the proper localization of centriolar satellites and
consequently ciliogenesis. This pro-proliferative pathway is
also conserved in SHH-type medulloblastoma, a pediatric
brain tumor arising from GCPs (Chang etal. 2019).
13.4 GABAergic Neurogenesis
GABAergic neurons are produced starting from Ptf1-a+ VZ
progenitors according to a two-step process (reviewed in
Carletti and Rossi 2008). First, projection neurons (nucleoolivary CN neurons and PCs) are generated locally, from fate
committed precursor populations. Secondly, some
progenitors become restricted to interneuron identities and
emigrate from the VZ to the nascent cerebellar nuclei or cortical layers, where they will acquire nal phenotypic identities under the inuence of environmental instructive cues.
Nucleo-olivary CN neurons are generated between E10.5
and E12.5 in the mouse cerebellar primordium and follow
the same migratory pathway as their glutamatergic counterparts (Palay and Chan-Palay 1974). PC progenitors undergo
their terminal mitosis between E11 and E13 and populate
different cortical regions according to their birthdate (Altman
and Bayer 1997). Postmitotic PCs migrate radially toward
the prospective cortex, where they form the multicell-thick
Purkinje cell plate (Morales and Hatten 2006). As early as
E14–15, they aggregate in clusters and nally align into a
monolayer through a process that is completed around P4
(Altman and Bayer 1997). The double-step migration allows
the anteroposteriorly migrating PCs to constitute the adult
parasagittal stripes, characterized by the expression of specic markers, that achieve a stable pattern in the third postnatal week (Larouche and Hawkes 2006; Consalez and
Hawkes 2013).
GABAergic interneurons comprise multiple subsets of
morphologically and neurochemically distinct phenotypes
integrated at different levels of the cerebellar cortex and
CN.These cells are produced from late embryonic life to the
second postnatal week; the peak is around P5 and the production of 75% of all inhibitory interneurons occurs prior to
P7 (Weisheit etal. 2006). The origin of these cells has been
controversial for a long time. Until a few years ago, molecular layer (ML) interneurons were thought to derive from the
EGL, the only germinal layer known to be active during
postnatal development (Ramón y Cajal 1911; Altman 1972).
More recently, analysis of chick-quail chimeras, transplantation experiments and retroviral injections demonstrated that
EGL exclusively generates granule cells, suggesting that ML
interneurons derive from the VZ (Hallonet etal. 1990; Gao
and Hatten 1994; Zhang and Goldman 1996a, b; Napieralski
and Eisenman 1993). Marichich and Herrup (1999) identied the progenitors of inhibitory interneurons as a population of Pax2+ cells, which appear in the VZ around E12 and
later emigrate into the cerebellar parenchyma. Inhibitory
interneuron precursors continue to proliferate during their
migration in the PWM (Zhang and Goldman 1996a; Weisheit
etal. 2006; Leto etal. 2006) and they generate interneuron
phenotypes according to an inside-out progression. CN interneurons are the rst to be born during embryonic and early
postnatal life, followed by granular layer (GL) interneurons
(Golgi and Lugaro cells) and, nally, by ML ones (basket
and stellate cells) (Weisheit etal. 2006; Maricich and Herrup
1999; Leto etal. 2006; Sudarov etal. 2011). Transplantation
experiments have demonstrated that all types of cerebellar
inhibitory interneurons derive from a single population of
multipotent progenitors that acquire mature phenotypic traits
under the inuence of local instructive cues provided by the
PWM microenvironment (Leto etal. 2006, 2009). It has been
shown that proliferative progenitors of GABAergic interneurons in the PWM are PTF1A+ cells that start expressing Pax2
during their last S phase (Maricich and Herrup 1999; Leto
et al. 2009; Fleming et al. 2013). Importantly, it has been
recently demonstrated that SHH delivered by PCs maintains
the PWM niche and sustains the proliferation of neural-stemcell-like primary progenitors able to generate both CD15+
astroglial precursors and PTF1A+ GABAergic interneuron
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progenitors (Fleming et al. 2013). The same morphogen
secreted by the choroid plexi in the embryonic cerebrospinal
uid is critically involved in the amplication of early
VZ-derived GABAergic progenitors (Huang et al. 2010),
suggesting that similar inuences could sustain neurogenesis
in the embryonic and postnatal cerebellum.
13.5 Neurogenesis andPurkinje Cell Type
Specication
A PTF1A → neurogenin 1/2 (Neurog1/2) → Early B-cell
factor 2 (EBF2) regulatory network is implicated in PC subtype specication (Zordan etal. 2008; Florio etal. 2012). By
this model, the early-born PC cohort expresses neither
Neurog1/2 nor Ebf2, and expresses the zebrin II (ZII+) phenotype in the adult. Soon after E11, Neurog1 and 2 are
upregulated by PTF1A in the later-born PC progenitors (e.g.,
Henke etal. 2009). In this context, Neurog2 regulates cell
cycle progression, neuronal output, and early dendritogenesis in PC progenitors (Florio etal. 2012), but neither Neurog1
nor 2 deletions affect the specication of PC subtypes
(Hawkes, unpublished observation). In turn, late-born PC
precursors express Ebf2, which represses the ZII+ phenotype
(Chung etal. 2008; Croci etal. 2006): Ebf2 deletion results
in transdifferentiated PCs that express markers characteristic
of both the ZII+ and ZII− subtypes– the only manipulation
known to alter a PC subtype phenotype. In addition, EBF2
plays a subtype-specic anti-apoptotic role in ZII− PCs by
locally regulating Igf1 gene expression (Croci etal. 2011).
As a result of these events, early-born PCs become ZII+ in
the adult, while late-born PCs adopt the ZII− phenotype.
Interestingly, a molecular interactor of EBF transcription
factors known as ZFP423 has been implicated in PC neurogenesis. Among other locations, this protein is expressed in
progenitors of the cerebellar ventricular zone, where it regulates the response to DNA damage and the maintenance of
the stem cell progenitor pool (Casoni et al. 2017).
Interestingly, ZFP423 is also required for hindbrain choroid
plexus development (Casoni etal. 2020). The hindbrain choroid plexus has been implicated in the control of cerebellar
VZ neurogenesis through SHH secretion (see above, Huang
etal. 2010).
13.6 Concluding Remarks
Different strategies active within cerebellar neurogenic
niches determine the precise sequence of phenotype generation: projection neurons are produced by dened pools of
fate-restricted progenitors, whose specication programs
mainly develop early in embryogenesis, while interneuron
precursors proliferate until the second postnatal week,
acquiring mature phenotypes under the inuence of local
instructive cues. The cellular/molecular mechanisms underlying these processes remain to be claried, as the biological
signicance of the diverse differentiation strategies. It is possible that these different mechanisms might support the correct establishment of topographically patterned long- distance
connections on one side and local experience- dependent networks on the other. Further analysis will be required to fully
address these questions.
Acknowledgements We thank Ketty Leto for her past contribution to
this work.
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Zones andStripes
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CarolArmstrong andRichardHawkes
14
Abstract
The cerebellar cortex is built around different classes of
Purkinje cell, which form distinct anterior–posterior
transverse zones, each of which is further divided into
parasagittal stripes. There are >200 stripes, which are
reproducible between individuals and fundamentally conserved across birds and mammals. Other features of cerebellar organization, including the topography of afferent
projections and cerebellar interneurons and glial cells, are
built around the Purkinje cell framework. Zone-and-stripe
architecture is established early in cerebellar development. Purkinje cells are born between embryonic day
(E)10 and E13 (in mouse) in the ventricular zone of the
fourth ventricle (VZ). Purkinje cell subtype specication
likely happens at this time. Postmitotic Purkinje cells
migrate via the cerebellar plate into the cerebellar anlage
and form a stereotypical array of clusters (E14–E18).
Clusters are the forebears of the stripes and the targets of
ingrowing afferent projections, and thereby determine the
afferent topography. In addition to ingrowing afferents,
Purkinje cell clusters are likely also mustering points for
subsets of glial cells and interneurons (and eventually
migrating granule cells) and so can be considered as topographical organizing centers (TOCs). Reelin signaling at
around birth triggers the rostrocaudal dispersal of the
clusters into the adult stripes. In parallel, phenotype
C. Armstrong (*)
Department of Biology, Mount Royal University,
Calgary, AB, Canada
Department of Cell Biology and Anatomy, Hotchkiss Brain
Institute, Cumming School of Medicine, University of Calgary,
Calgary, AB, Canada
e-mail: carmstrong@mtroyal.ca
R. Hawkes
Department of Cell Biology and Anatomy, Hotchkiss Brain
Institute, Cumming School of Medicine, University of Calgary,
Calgary, AB, Canada
e-mail: rhawkes@ucalgary.ca
specication in the upper rhombic lip forms distinct subpopulations of granule cell precursors that migrate over
the embryonic cerebellar surface and show restriction at
the underlying Purkinje cell cluster boundaries. When the
postmitotic granule cells migrate and settle in the granular
layer, this topography is retained. This complex topographical organization of Purkinje cells, granule cells,
and afferents is further reected in the cerebellar functional map and explains the patterned distribution of many
cerebellar pathologies.
Keywords
Cerebellum · Purkinje cell · Zebrin · Climbing ber
Mossy ber · Granular layer · Pattern formation
14.1 Adult Zones andStripes
The cerebellar cortex is traditionally described as comprising lobes and lobules separated by ssures. However, lobulation does not reect the functional organization of the
cerebellum, its connectivity, or its embryology. A more fundamental architecture is shown by intrinsic differences
between subsets of Purkinje cells (PCs), seen through the
expression of molecular markers such as zebrin II/aldolase C
(Brochu etal. 1990), the small heat shock protein (HSP)25
(Armstrong et al. 2000) and phospholipase C (PLC)β4
(Sarna etal. 2006: see Fig.14.1). These reveal an elaborate
and reproducible pattern of transverse zones and parasagittal
stripes that is the scaffold around which the rest of the cerebellar cortex is organized (reviewed in Apps etal. 2018).
The mammalian cerebellum comprises at least ve transverse zones (Fig. 14.1): regions of the cerebellar cortex,
ranging from anterior to posterior and distinguished as distinct expression domains. The boundaries between transverse zones do not align with classical anatomical boundaries
such as lobules. The anterior zone (AZ) is roughly equivalent
to lobules I–V (“roughly” because transverse zones inter-
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_14
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Fig. 14.1 Zones and stripes.
Newborn Purkinje cells (PCs)
exit the ventricular zone (VZ)
and stack by birthdate.
Subsequently, they migrate to
form a symmetrical array of
clusters. Reelin-disabled
signaling triggers cluster
dispersal into the adult
transverse zones [anterior
zone (AZ), central zone A and
B (CZa, CZb), posterior zone
(PZ), nodular zone (NZ)] and
parasagittal stripes (seen here
in an adult mouse transverse
section immunoperoxidasestained for PLCβ4: Sarna
etal. 2006). Mutations in the
Reelin→Dab1 pathway, both
in human and mouse, result in
a failure of PC cluster
dispersal with consequent
ataxia
C. Armstrong and R. Hawkes
digitate). The central zone (CZ) comprises lobules VI and
VII and can be further divided into an anterior CZa (~lobule
VI) and a posterior CZp (~lobule VII). The posterior zone
(PZ) occupies lobule VIII and the dorsal half of lobule
IX.The nodular zone (NZ) includes the ventral half of lobule
IX and lobule X.In birds (Pakan etal. 2007; Marzban etal.
2010) and bats (Kim etal. 2009), a sixth transverse zone–
the lingular zone (LZ)– has been identied in lobule I.
Within each transverse zone, PCs are further divided
into stripes arranged mediolaterally across the vermis and
hemispheres (reviewed in Armstrong and Hawkes 2013:
Fig.14.1). For example, alternating stripes of zebrin II+/−
PCs are found in the AZ and PZ (Hawkes and Leclerc
1987; Brochu et al. 1990), and HSP25+/− stripe arrays
are found in the CZ and NZ (Armstrong et al. 2000).
However, no single marker reveals the full complexity of
the cerebellar architecture: distinct stripes shown by one
marker are revealed as a composite with another. For
example, zebrin II−/PLCβ4+ stripes in the AZ are subdivided by L7/pcp2-lacZ expression (Ozol etal. 1999), and
zebrin II+ stripes are subdivided by HSP25in the PZ during development (Armstrong etal. 2001) and the NZ in
the adult (Armstrong etal. 2000: reviewed in Armstrong
and Hawkes 2013).
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The intrinsic zone-and-stripe organization of the cerebellar cortex is not restricted to PCs– it also encompasses granule cells, inhibitory interneurons (Consalez and Hawkes
2013), glial cells (e.g., Scott 1964; Eisenman and Hawkes
1989), and afferent terminal elds (e.g., Voogd and Ruigrok
2004). Granule cells expression boundaries in the adult gran-
ular layer and the developing external granular layer (EGL)
align with the PC transverse boundaries (reviewed in
Consalez etal. 2021). Similarly, several granule cell mutation phenotypes are restricted to a particular transverse zone.
For instance, in the meander tail mutant (meaJ), the AZ lacks
granule cells (Hamre and Goldowitz 1997) while in contrast
a Neurod1 deletion results in an apparently normal granular
layer in the AZ, but a reduction of granule cells in the CZ and
a complete lack of granule cells in the PZ and NZ (Miyata
etal. 1999). At the other extreme, several markers (e.g., neuronal nitric oxide synthase (nNOS) and dystrophin: reviewed
in Consalez etal. 2021) reveal several thousand reproducible
“patches” in the granular layer that in turn may represent the
topographical “quantum” of cerebellar action (reviewed in
Apps etal. 2018).
Next, inhibitory interneurons also align with PC stripes.
For example, Golgi cell dendrites in the molecular layer are
restricted at PC stripe boundaries (Sillitoe etal. 2008) and
the expression of neurolament antigens by basket cells is
striped and in register with the PC expression of zebrin II
(reviewed in Consalez and Hawkes 2013). In the latter case,
the alignment appears to be secondary to PC activity (Zhou
et al. 2020). Similarly, unipolar brush cells are primarily
restricted to the NZ, and within this transverse zone,
calretinin- expressing unipolar brush cells are organized into
parasagittal stripes that align with zebrin II-expressing PCs
(Dino etal. 1999; Chung etal. 2009).
Glial cells also show a zone-and-stripe organization. For
instance, VZ glial progenitors in chick are organized into
parasagittal clonal stripes (Lin and Cepko 1999); a subset of
neuropeptide Y-expressing Bergmann glia is restricted to the
CZ and NZ, and within these transverse zones form parasagittal stripes that align with HSP25+ PCs (Armstrong etal.
2000; Reeber etal. 2018); and 5′-nucleotidase expression by
Bergmann glial bers precisely mirrors the PC zebrin expression pattern (Eisenman and Hawkes 1989).
Finally, afferent tract tracing has shown that both climbing ber and mossy ber afferent terminal elds are
restricted to specic stripes (reviewed in Ruigrok 2011).
For example, climbing bers originating in the inferior
olive terminate selectively on the PC somata and proximal
dendrites within parasagittal stripes of zebrin II+/− PCs
and similarly, mossy ber terminal elds in the granule cell
layer of the vermis align with specic zebrin II+/− (e.g.,
Sugihara and Shinoda 2004; Voogd and Ruigrok 2004) and
HSP25+/− (Armstrong et al. 2009) PC stripes. Finally,
although less striking than the mossy and climbing ber
topography, noradrenergic afferents to the molecular layer
also show a clear bias toward a parasagittal orientation
(Longley etal. 2021).
The importance of the architecture is further emphasized
by its evolutionary conservation: things that are conserved
are important. The same zone-and-stripe pattern is found in
all mammals (>20 species: Sillitoe etal. 2005; Marzban and
Hawkes 2011) and birds (4 species: Pakan et al. 2007;
Iwaniuk et al. 2009; Marzban et al. 2010; Coreld et al.
2015) studied to date. Distinct zebrin II+/− PC phenotypes
and/or evidence of stripes are also found in sh and reptiles
(Meek etal. 1992; Wylie etal. 2016). However, although the
basic ground plan is conserved transverse zone sizes vary
widely, consistent with ecological diversity and mosaic evolution. Thus, in bats, the CZ, which receives mossy ber
innervation associated with sonar, is greatly enlarged (Kim
etal. 2009), whereas in blind mammals such as naked mole
rats (Marzban et al. 2011) and star-nosed moles (Marzban
et al. 2015), the CZ and NZ, zones which receive visual
inputs, are unusually small.
14.2 Pattern Formation
The zone-and-stripe architecture seen in the adult cerebellum is established during development. It arises from the
coordinated interactions of two germinal zones: the VZ that
produces the GABAergic neurons (PCs and inhibitory interneurons) and the upper rhombic lip that produces the glutamatergic granule cells and unipolar brush cells (reviewed in
Dastjerdi etal. 2012; Hashimoto and Hibi 2012; Galas etal.
2017; Consalez etal. 2021).
14.2.1 Pattern Formation intheVentricular
Zone (VZ)
PCs undergo terminal mitosis (E10–E13in mice: Miale and
Sidman 1961) within a Ptf1a+ expression domain in the VZ
(Hoshino etal. 2005; Zordan etal. 2008) and migrate dorsally to form the transient cerebellar plate by E14. At this
stage, PC progenitors and glial precursors (but not cerebellar
interneurons) express the transcription factor early B cell
factor 2 (Ebf2: Badaloni et al. 2019). Within a few days,
Ebf2 is suppressed in a subset of PCs that is born early and
destined to become zebrin II+ but maintained in PCs that are
born later and destined to become zebrin II−/Ebf2+ [Ebf2
acts to specify the zebrin II− phenotype by suppressing
expression of the zebrin II+ phenotype (Chung etal. 2008)].
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E18E14 P20
E10-13
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C. Armstrong and R. Hawkes
Birthdating studies also reveal a direct correlation between
PC birthdates and their nal zone-and-stripe location, suggesting that both subtype specication and positional information are acquired at this stage (e.g., Karam et al. 2000;
Hashimoto and Mikoshiba 2003; Chung etal. 2008; Namba
etal. 2011).
Between E14 and E17, PCs in the cerebellar plate undergo
a choreographed migration to create a reproducible array of
some 50 clusters (Vibulyaseck etal. 2017) that can be distinguished based on differential gene expression (reviewed in
Armstrong and Hawkes 2013). These clusters serve as topographic organizing centers (TOCs)– mustering yards for the
cerebellar components (afferents, interneurons, glial cells)
that will form the adult stripes (Fig.14.2).
GABAergic interneurons– basket and stellate cells of the
molecular layer and Golgi cells of the granular layer, etc.–
are also born from a common progenitor pool in the VZ
(Leto etal. 2006; Sudarov etal. 2011). From the VZ, they
enter the immature white matter through which they migrate
while continuing to divide (so-called transit amplication)
until joining the PC clusters (Fig.14.2; Sudarov etal. 2011;
Schilling 2018). Once the PC clusters begin to disperse and
lobules appear, the interneurons are carried along. Because
dispersal is restricted to the rostrocaudal axis, and involves a
>20-fold extension, each cluster is drawn out into a long,
parasagittal stripe. The interneuron axons and dendrites are
also drawn out along with the PCs and as a result, cerebellar
interneurons show a parasagittal orientation and their pro-
TOC
MFs
CFs
TOC
INs
Z- Z+
VZ
Fig. 14.2 The development of topographical organizing centers
(TOCs) in the developing cerebellum. Purkinje cell (PC) precursors
arise from the ventricular zone (VZ) and undergo an elaborate rearrangement into ~50 multilayered clusters [future zebrin+ (Z+) or
zebrin− (Z−)]. These serve as topographical organizing centers (TOCs),
mustering the afferent inputs [mossy bers (MF) and climbing bers
(CF) and GABAergic interneurons (INs)] that comprise the adult cerebellar cortical stripe. As the PC clusters disperse into long stripes, all
other components disperse along with them, thereby adopting a parasagittal architecture while remaining conned to their individual cluster/stripe
PCs
cesses show restriction at stripe boundaries (reviewed in
Consalez and Hawkes 2013).
PC clusters are also the embryonic targets of the cerebellar afferents (Fig.14.2). Afferent topography is established
around E15–E16 (Paradies and Eisenman 1993; Grishkat
and Eisenman 1995) presumably by chemospecic mapping
on PCs at the cluster stage (reviewed in Rahimi-Balaei etal.
2015; Lackey and Sillitoe 2020): thus, the TOCs include
both climbing and mossy ber afferents that respect the
nascent PC stripe topography (e.g., Wilson et al. 2019).
Mossy ber afferents are varied with respect to origin and
timing of innervation but do form a transitory relationship
with particular PC clusters. As the granular layer matures,
the mossy ber terminals detach from the PCs and connect
with local postmitotic granule cells. This preserves the alignment of mossy ber terminal elds and the overlying PC
stripes.
14.2.2 Pattern Formation intheRhombic Lip
During early embryogenesis, all granule cells are derived
from an atonal (Atoh1+) lineage in the upper rhombic lip,
which expands to cover the cerebellar surface as the EGL
(reviewed in Consalez etal. 2021). Within the EGL at least
three transverse granule cell progenitor zones are identied
by gene expression, with boundaries aligned with the underlying PC zones (Fig. 14.3). For example, homeobox transcription factors reveal that different EGL expression
domains overlay the AZ and the CZ (e.g., Lmx1a expression
distinguishes AZ from CZ (Chizhikov etal. 2010) while Tlx3
distinguishes the PZ from the NZ (Logan etal. 2002)). The
same boundaries are revealed by birth dating– early born
granule cell progenitors (Lmx1a−) form the anterior EGL,
while later born progenitors (Lmx1a+) form the posterior
EGL (Fig.14.3). The PC cluster-EGL boundary alignments
suggest that granule cell progenitor dispersal is restricted at
PC transverse zone boundaries.
Once postmitotic, granule cells migrate from the EGL to
the granular layer guided by Bergmann glial bers. In this
way, the EGL topography is projected into the nascent granular layer. Secondary patterning of the granular layer happens postnatally and involves formative interactions with
both PCs and mossy ber afferents (e.g., reviewed in
Consalez etal. 2021). Under the inuence of the mossy ber
afferents via nNOS signaling, an elaborate patch topography
evolves in the granular layer, comprising several thousand
discrete patches, each consisting of a few dozen PCs and
their associated interneurons and mossy ber afferents
(reviewed in White etal. 2014; Consalez etal. 2021). Similar
patches are found in recordings of the trigeminal afferent
sensory elds (Welker 1976: reviewed in Apps etal. 2018).
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Fig. 14.3 Distinct
populations of progenitors in
the external granule cell layer.
A rst wave of Lmx1a− /
Otx1+ granule cells creeps
across the surface of the
cerebellar cortex to form the
(red) EGL situated above the
AZ PCs. A second wave (teal)
of Lmx1a+/Otx1/2+ granule
cells follow suit but stops at
the A/-CZ transverse zone
boundary seen in the adult.
The Lmx1a+ granule cells
will populate the granular
layers of the CZ, PZ, and
NZ.A third boundary of Tlx3
expression is seen in the EGL
and correlates with the PZ/NZ
boundary
Lmx1aEbf2+
Otx1+
Tlx3+
AZ
14.3 Pattern Formation ofAerent
andEerent Projections
As noted above, the afferent topography of the cerebellar
cortex is established in the TOCs. Perinatally, climbing
bers have already entered specic clusters and synapsed on
the PC somata (Sotelo and Wassef 1991). Similarly, mossy
bers make transient connections with the PCs in the clusters. Later, as Reelin signaling triggers cluster dispersal into
the adult stripe, the afferents disperse along with them. As
the stripes mature, climbing bers rene their projections by
the elimination of supernumerary connections (Kano etal.
2018) and mossy bers detach from the PCs and form new
synaptic connections with local granule cells and interneurons, thus generating the striped afferent pathways. Finally,
the topographical distribution of corticonuclear efferents
from PCs to the cerebellar nuclei and medial and lateral vestibular nuclei is quite complex (e.g., there are at least six
distinct compartments in the medial nuclei alone: Chung
etal. 2009: see also Kebschull etal. 2020) but broadly the
projections are organized from medial to lateral (Ruigrok
2011; Sugihara 2011).
14.4 Functional andClinical Implications
The fact that zone-and-stripe architecture is conserved across
species and manifested in the topography of afferents, cortical neurons, and efferents strongly suggests that it has important functional and clinical implications. However, the
functional and clinical signicance of cerebellar architecture
has only recently begun to be revealed. For example, several
studies have identied intrinsic functional differences
between PC subtypes and shown that the spiking activity of
Lmx1a+
Ebf2Otx1/2+
Tlx3+
PZ
CZ
NZ
Tlx3-
PCs is correlated with their zebrin II+/− phenotype (White
etal. 2014; Xiao etal. 2014; Zhou etal. 2014). In particular,
resting simple-spike ring activity differs between zebrin
II+/− PCs with zebrin II+ PCs ring action potentials at a
lower rate and frequency (60Hz) than zebrin II− (90Hz)
PCs, even though the cells are directly adjacent. This difference is intrinsic and independent of synaptic input (Xiao
etal. 2014; Zhou etal. 2014). These functional differences
may be linked to the activity of a transient receptor potential
cation channel type C3 (TRPC3) that is associated with
zebrin II− PCs, as blocking TRPC3 decreased PC ring frequency (Zhou etal. 2014). In a similar fashion, modulation
of PC complex-spike activity in PC in the avian cerebellum
shows that zebrin II+/− PCs respond differently to optic ow
(Long etal. 2018).
Cerebellar patterning also shows up in instances of cerebellar learning. As an example, cerebellar circuits are crucial
to various aspects of ocular motor control including eyeblink
conditioning and vestibular-ocular responses. Each of these
types of motor learning has been associated with different
PC subsets: long-term depression (LTD), or a decrease in
synaptic strength, as seen in eyeblink conditioning is typically associated with zebrin II− PCs (De Zeeuw and Ten
Brinke 2015), while long-term potentiation (LTP), or an
increase in synaptic strength, as seen with vestibular-ocular
responses is associated with zebrin II+ PCs (Voges et al.
2017). Furthermore, goal-directed, or reward-response
behaviors are also positively correlated to PC stripes: when
mice conditioned to associate a 10Hz tone with a reward,
climbing ber activation was predominantly seen in the
zebrin II+ stripes (Tsutumi et al. 2019). Functional differences in the expression of LTD between stripes are mirrored
in molecular differences in the molecular pathways believed
to underpin them (Hawkes 2014). For instance, synaptic
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C. Armstrong and R. Hawkes
plasticity at the parallel ber-PC dendrite synapse can be
modulated by cannabinoid receptor 1 which is restricted to
differentiating granule cells in the AZ and CZa, suggesting
selective functional and topographical pathways within the
cerebellar endocannabinoid signaling system (Martinez etal.
2020).
Finally, the zone-and-stripe architecture has clinical
implications for cerebellar pathologies (typically ataxias).
For example, developmental failures of cell migration that
result in abnormal cerebellar architecture are routinely
accompanied by ataxia. As noted in Fig.14.1, the transformation of the embryonic PC clusters into adult stripes is triggered by the Reelin → Dab1 signaling pathway and mutations
result in a failure of PC cluster dispersal, abnormal adult patterning, and ataxia (reviewed in Lee and D’Arcangelo 2016).
Similarly, patterned pathology is seen in the wide range of
insults and genetic defects that result in PC death. Indeed, in
a survey of PC death phenotypes, a great majority showed a
preferential sensitivity of one PC subtypes or another and
consequently zone or stripe restricted PC loss (reviewed in
Sarna and Hawkes 2003).
In summary, while the rst functional implications of the
zone-and-stripe architecture are beginning to emerge, the
broader implications of this complex and intricate topography remain largely unknown. It is expected that future iterations of this chapter will include much more of the functional
signicance of the zone-and-stripe organization of the
cerebellum.
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