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Specification ofCerebellar Neurons
https://t.me/medicina_free
SatoshiMiyashita andMikioHoshino
15
Abstract
The cerebellum consists of about ten types of neurons that
have distinct characteristics in terms of their location,
morphology, immunoreactivity and physiology. They can
be categorized into two groups; glutamatergic excitatory
and GABAergic inhibitory neurons. Excitatory neurons
are comprised of glutamatergic deep cerebellar nuclei
(DCN) neurons, granule cells and unipolar brush cells
(UBCs). Inhibitory neurons include GABAergic DCN
neurons, Purkinje cells, Golgi cells, Lugaro cells, basket
cells, and stellate cells. GABAergic DCN neurons are
interneurons that contribute to local circuitry and projection neurons that extend axons toward the inferior olivary
nucleus. As all cerebellar GABAergic interneurons
express Pax2 (Maricich and Herrup J Neurobiol 41:281–
294, 1999), they are called Pax2+ interneurons (Pax2+
INs). Recent studies have partly uncovered the molecular
machinery for neuronal subtype specication in the
cerebellum.
Keywords
Neural progenitor · Rhombic lip · Ventricular zone
Glutamatergic · GABAergic · bHLH · Transcription
factor · Spatiotemporal regulation
S. Miyashita
Department of System Pathology for Neurological Disorders,
Brain Research Institute, Niigata University,
Niigata-shi, Niigata, Japan
Institute for Research Promotion, Niigata University,
Niigata, Japan
e-mail: s.miyashita@bri.niigata-u.ac.jp
M. Hoshino (*)
Department of Biochemistry and Cellular Biology, National
Institute of Neuroscience, National Center of Neurology and
Psychiatry, Kodaira, Tokyo, Japan
e-mail: hoshino@ncnp.go.jp
15.1 Birthplaces andBirthdates
ofCerebellar Neurons
The cerebellum consists of about 10 types of neurons that
have distinct characteristics in terms of their location, morphology, immunoreactivity, and physiology. They can be categorized into two groups: glutamatergic excitatory and
GABAergic inhibitory neurons. Excitatory neurons are comprised of glutamatergic deep cerebellar nuclei (DCN) neurons, granule cells, and unipolar brush cells (UBCs).
Inhibitory neurons include GABAergic DCN neurons,
Purkinje cells, Golgi cells, Lugaro cells, candelabrum cells,
basket cells, and stellate cells. GABAergic DCN neurons are
interneurons that contribute to local circuitry and projection
neurons that extend axons toward the inferior olivary nucleus.
As all cerebellar GABAergic interneurons express Pax2
(Maricich and Herrup 1999), they are called Pax2+ interneurons (Pax2+ INs).
All neurons in the cerebellum emerge from the cerebellar
neuroepithelium which includes the dorsally located rhombic lip (RL) and the ventrally located ventricular zone (VZ).
In the cerebellum, the RL produces all glutamatergic neurons (Ben-Arie etal. 1997; Machold and Fishell 2005; Wang
et al. 2005). The VZ generates all GABAergic neurons
(Hoshino et al. 2005), although postnatally produced neurons, such as stellate and basket cells, do not directly emerge
from the VZ but from the prospective white matter (PWM)
thought to be derived from the VZ (Leto etal. 2009).
Birthdates of GABAergic neurons can be estimated by
BrdU or tritium incorporation studies or adenoviral infection
studies (Chan-Palay etal. 1977; Batini etal. 1992; De Zeeuw
and Berrebi 1995; Sultan et al. 2003; Leto et al. 2006;
Hashimoto and Mikoshiba 2003). In mice, Purkinje cells are
generated at embryonic day (E) 10.5–E13.5, GABAergic
DCN neurons at E10.5–E11.5, and Golgi cells at approximately E13.5~postnatal (peak around E13.5–E15.5). Lateborn GABAergic neurons, including stellate and basket cells,
emerge from GABAergic progenitor cells in the PWM at
© 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_15
107
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S. Miyashita and M. Hoshino
later stages (approximately E13.5~perinatal, peak around
E17.5 ~ perinatal). Somatic recombination-based clonal
analyses have revealed that Purkinje, Golgi, and
basket/stellate cells belong to the same lineage (Mathis etal.
1997; Mathis and Nicolas 2003). This suggests that not only
Purkinje and Golgi cells but also GABAergic progenitors in
the PWM are derived from the VZ.As to glutamatergic neurons, glutamatergic DCN neurons leave the RL at early
stages (E10.5–12.5) and granule cells and UBCs at middle to
late stages (granule cells; E13.5~, UBCs; E13.5–E18.5)
(Machold and Fishell 2005; Wang etal. 2005; Englund etal.
2006).
15.2 Molecular Machinery toSpecify
Distinct Types ofCerebellar Neurons
Two basic helix–loop–helix proteins are involved in the
specication of glutamatergic vs. GABAergic neurons.
Atoh1 (also called Math1) is expressed in the RL and
involved in producing glutamatergic neurons (Ben-Arie etal.
1997; Machold and Fishell 2005; Wang etal. 2005). Ptf1a is
expressed in the VZ and species the GABAergic neuron lineage (Hoshino et al. 2005; Pascual et al. 2007). When the
expression of Atoh1 and Ptf1a is switched, the RL and the
VZ produce GABAergic and glutamatergic neurons, respectively (Yamada etal. 2014), suggesting that these two bHLH
proteins are sufcient to specify glutamatergic and
GABAergic fates. These observations imply that neural progenitors in the RL and the VZ have spatially regulated distinct identities to produce glutamatergic and GABAergic
neurons, respectively.
At early neurogenesis stages such as E11.5, there are two
types of GABAergic neuron progenitors in the VZ that
express Ptf1a; Pax2+ IN-producing progenitors (PIPs) and
Purkinje cell-producing progenitors (PCPs). PIPs and PCPs
express transcription factors, Gsx1 (also called Gsh1) and
Olig2, respectively. At the early stages, only a small number
of PIPs are located at the ventral most region within the VZ
and a large number of PCPs occupy the remaining regions in
the VZ.As development proceeds, PCPs gradually transit to
become PIPs starting from ventral to dorsal regions. This
temporal identity transition of cerebellar GABAergic neuron
progenitor causes the loss of PCPs in the VZ by E14.5, correlating with the observations that Purkinje cells are produced
only at early neurogenesis stages (E10.5–E13.5). Therefore,
it was assumed that the temporal identity transition of cerebellar GABAergic neuron progenitors from PCPs to PIPs is
negatively regulated by Olig2 and positively by Gsx1, which
may contribute to proper numbers of distinct subtypes of neurons being produced (Seto etal. 2014). In contrast, recent lineage trace analyses have reported that Olig2 lineage cells
derived from the VZ seem to mainly give rise to the Purkinje
cells (Ju et al. 2016; Lowenstein et al. 2021). Lowenstein
et al. have also found that Olig3 is expressed in newborn
Purkinje cells or “fate-committed Purkinje cell precursors”
and regulate the specication of Purkinje cells by suppressing
the Pax2 expression together with Olig2. It is still unknown
whether GABAergic projection neurons in the DCN are
derived from PCPs or PIPs is unknown.
Considering the birthdates of distinct Pax2+ INs, PIPs
may rst produce GABAergic interneurons in the DCN
(E10.5~), and then generate Golgi cells (E13.5~). PIPs at late
neurogenesis stages may give rise to progenitor cells in the
PWM that eventually generate stellate, basket cells, and candelabrum cells (Sudarov etal. 2011). Previous transplantation
studies suggested that distinct Pax2+ Ins are derived from the
same progenitor pool and that extrinsic instructive cues in the
microenvironment may affect the terminal neuronal type
commitment. One candidate for the cue may be sonic hedgehog (SHH) (Fleming et al. 2013; De Luca et al. 2015). In
addition, Lhx1 and Lhx5 as well as their cofactor Lbd1 are
known to postmitotically participate in Purkinje cell differentiation (Zhao etal. 2007). Recently, it was reported that transcription factors, Tfap2A and Tfap2B, are involved in the
specication of Pax2+Ins (Zainolabidin etal. 2017).
In contrast to GABAergic neurons, the machinery to specify each cerebellar glutamatergic neuron subtype remains elusive. Some transcription factors, such as Tbr1, Irx3, Meis2,
Lhx2, Lhx9, and Olig2 are expressed in subsets of postmitotic progenitors of glutamatergic DCN neurons, but their
function is still unclear (Morales and Hatten 2006; Seto etal.
2014). As to granule cells, it is known that intrinsic and
extrinsic molecules such as Zic1, Meis1, and SHH play
important roles in cell migration, differentiation, and survival
(Aruga etal. 1998; Dahmane and Ruiz-i-Altaba 1999; Lewis
et al. 2004; Wallace 1999; Wechsler-Reya and Scott 1999;
Owa etal. 2018), but the cell-type specication machinery
remains to be identied. UBCs are another type of excitatory
interneurons in the cerebellar cortex, which strongly express
Tbr2 (Englund etal. 2006). Yeung etal. reported that the RL
is subdivided into two compartments by the Wls expression
and that UBCs may be originated from the boundary region
between the compartments (Yeung etal. 2014).
The molecular machinery to specify cerebellar neuronal
cell types is summarized in Fig. 15.1. Neuronal cell types
seem to be dened according to the spatiotemporal identities
of neural progenitors in the neuroepithelium. The bHLH
transcription factors, Atoh1 and Ptf1a, confer the spatial
identities of the RL and the VZ on neural progenitors, letting
them produce glutamatergic and GABAergic neurons,
respectively. Glutamatergic and GABAergic neuron progenitors in the RL and the VZ change their temporal identities to
produce distinct types of neurons during development.
Recent transcriptome analyses have powerfully advanced
our understandings of the machinery for cerebellar neuron
15 Specication ofCerebellar Neurons
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109
Fig. 15.1 Specication of
cerebellar neurons by
spatiotemporal regulation of
neural progenitor identities
Spatial Identities
of Progenitors
Glutamatergic
GABAergic
Ptf1a
VZ
specication and differentiation. They clearly visualize the
heterogenic populations in cerebellar neuron progenitors
within the EGL, RL, or the VZ, although characteristics of
each subset of progenitors are still elusive (Adachi etal. 2021;
Aldinger etal. 2021; Carter etal. 2018; Kozareva etal. 2021;
Peng etal. 2019; Vladoiu etal. 2019; Wizeman etal. 2019).
Comprehensive transcriptome analysis and invivo validations
will be required to fully understand the mechanisms underlying cerebellar neuronal type specication.
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Cerebellar Nucleus Development
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Hong-TingKwok andRichardJ.T.Wingate
16
Abstract
The cerebellar nuclei play a role in integrating cerebellar
cortical output with inputs from other brain regions. Made
up of a complex collection of both excitatory and inhibitory projection neurons as well as subtypes of interneurons, the cerebellar nuclei are developed from two
germinal regions, the rhombic lip and the ventricular
zone. In this chapter, we describe the developmental timeline of the cell types in relation to the development of the
rest of the cerebellum, and how although the gross nuclei
structures vary along the evolutionary tree, the cell types
within are mostly conserved across evolution.
Keywords
Cerebellar nuclei · Development · Rhombic lip
Ventricular zone · Rhombomere 1
The cerebellar nuclei (CN) are the nal output structures of
the cerebellum, integrating inputs from the forebrain, brainstem, and spinal cord with the cerebellar cortical output from
Purkinje cells. In contrast to the remarkably evolutionarily
conserved connectivity between granule cells and Purkinje
cells in the cerebellar cortex, the size, foliation, and number
of CN vary between animals (1in amphibians, 2in reptiles
and birds, and 3–5in mammals) (Nieuwenhuys etal. 1998).
In humans, there are four nuclei: the medial (fastigial), anterior and posterior interposed are classed as separate nuclei.
Historically, much of what is known concerning CN cell
morphologies and neuronal circuitry comes from Golgi and
Nissl preparations of the mammalian lateral nucleus observed
by light and electron microscopy (Chan-Palay 1977).
Neurotransmitter content and neuronal connectivity identied glutamatergic cells and three inhibitory cell classes.
Recent single-cell RNA analysis combined with anatomical
tracing identied that glutamatergic output cells are of two
different types but conrmed that there are two glycinergic
populations and a GABAergic inhibitory output neuron projecting to the inferior olive (Kebschull etal. 2020; Batini
et al. 1992; Chen and Hillman 1993; Fredette et al. 1992)
(Fig.16.1).
CN receive inhibitory projections from the Purkinje cells
from the overlying cerebellar cortex in a broadly topographic
manner. The lateral nuclei are innervated by the lateral cerebellum and medial nuclei by the medial vermis (Voogd and
Glickstein 1998). CN also integrate collateral inputs from
axons projecting from the pontine nucleus and inferior olive
to the cerebellar cortex (Fig.16.1). The output of each CN is
then directed to different central neural systems as determined by the pattern of their efferent connections (Larsell
and Jansen 1972). Of these, the connection from the lateral
nucleus to the ventrolateral thalamus is a uniquely mammalian adaptation and completes a closed-loop cortico-pontinecerebellar relay circuit (Kelly and Strick 2003) that is heavily
implicated in modulating higher cognitive function in
humans (Schmahmann 2010).
H.-T. Kwok · R. J. T. Wingate (*)
MRC Centre for Neurodevelopmental Disorders, King’s College
London, London, UK
e-mail: hongting_prekop@gis.a-star.edu.sg;
richard.wingate@kcl.ac.uk
© 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_16
111
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H.-T. Kwok and R. J. T. Wingate
Fig. 16.1 Connections and circuitry of the human lateral nucleus.
Left: The lateral CN receives input from Purkinje cells (PC) and innervates the thalamus, which in turn modulates cortical activity. The
nucleus also receives climbing bers (CF) collateral input from the
inferior olive (IO), and mossy bers (MF) collaterals, originating principally from the pons. Climbing and mossy bers terminate on PC and
granule cells (GC) in the cerebellar cortex, respectively. The CN also
16.1 Concepts ofCN Development Have
Changed Markedly inRecent Years
Cell types of the cerebellum arise from two germinal regions
within the most anterior neuromere of embryonic hindbrain,
rhombomere 1: the ventricular zone (VZ) and the rhombic
lip (RL). The VZ is a neuroepithelial zone that lines the dorsolateral part of the fourth ventricle, while the RL comprises
the interface of this neuroepithelium with the roof plate of
the fourth ventricle (Wingate 2001). Until the last decade, it
was thought that all CN neurons originate from the VZ then
migrate radially into the white matter (Altman and Bayer
1985a, b; Goldowitz and Hamre 1998). It is now known that
CN neurons of different neurotransmitter types are born
from both the RL and VZ.
Research by classical birth dating and genetic fate mapping has shown that all cerebellar excitatory neurons are
derived from RL progenitors, specied by the expression
of Atoh1, while inhibitory neurons arise from the VZ,
where progenitors are specied by the early expression of
Ptf1a (Hoshino etal. 2005). The bHLH proteins, Ptf1a and
Atoh1, have both been shown to be necessary (Machold
and Fishell 2005; Wang etal. 2005) and sufcient (Yamada
etal. 2014) for the production of all GABAergic and glutamatergic neurons in the cerebellum, respectively
contains GABAergic projection neurons that send inhibitory signals to
the IO.Right: Within the nucleus, each PC axon fans out into a cone
that innervates a number of excitatory and GABAergic projection neurons. Small GABAergic and glycinergic interneurons provide local
inhibition. Inputs from MF and CF collaterals run perpendicular to the
afferent Purkinje cell axons [adapted from (Chan-Palay 1977)]
(Fig.16.2). A small number of large glycinergic projection
neurons, which are only found in the medial nucleus
(Bagnall etal. 2009), are the exception, being potentially
derived from the RL despite being inhibitory (Kebschull
et al. 2020). The following description exemplies CN
development using the embryonic mouse model over its
21days of gestation.
16.1.1 Glutamatergic Neurons are Born at
theRhombic Lip
Atoh1-expressing progenitor cells from the RL produce glutamatergic CN projection neurons between embryonic day
(e)10–e12.5 prior to making granule cell precursors that
populate the external granule layer (EGL) (Machold and
Fishell 2005; Wang etal. 2005). From e12.5 to e14.5, the CN
cells migrate from the RL across the dorsal surface of rhombomere 1 via the subpial rhombic lip migratory stream
(RLS), then congregate at the nuclear transitory zone (NTZ)
at the boundary of the cerebellar anlage (Fig.16.2). The NTZ
is thought to be a transient differentiation zone (Altman and
Bayer 1985a), where nuclear neurons are dened by specic,
temporally restricted, developmental transcription factor
proles (Fink etal. 2006).
16 Cerebellar Nucleus Development
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113
Fig. 16.2 Cerebellar nucleus neurons have a dual origin. Different
neuronal subtypes in the cerebellum develop from separate germinal
regions. Precursors continue to migrate, proliferate, differentiate, and
mature postnatally. The CN glutamatergic cells form rst at the RL and
migrate via the nuclear transitory zone (NTZ). CN GABAergic projection neurons are also born early and migrate to the ventral part of the
The CN are born in a lateral to medial sequence subsequent to the rst-born RL derivatives, which become extracerebellar neurons (Machold and Fishell 2005). Like these
extra-cerebellar neurons, nuclear cells in the lateral nucleus
of mammals express the LIM-homeodomain gene Lhx9
(Wang et al. 2005; Green and Wingate 2014). Both these
early populations project to the thalamus suggesting a role
for Lhx9 in specifying axonal projection (Green and
Wingate 2014). Subsequently, RL-derived projection neurons of the interposed and medial nuclei are dened by their
expression of Tbr2 and Tbr1, respectively (Fink etal. 2006;
Engelkamp etal. 1999; Landsberg etal. 2005) and extend
axons to various hindbrain, midbrain, and ventral diencephalic targets.
From e14.5 to e16.5, CN cells in the NTZ descend into
the white matter. It is unclear whether this is due to active
migration toward the VZ (Altman and Bayer 1985a) or displacement by gross morphogenic changes to cerebellar shape
as granule cell precursors in the EGL proliferate to produce
the most abundant neuronal population in the brain.
NTZ.The RL then gives rise to granule cell precursors, which form the
external granule layer (EGL) that later migrates in to form the internal
granule layer (IGL). All cortical GABAergic cells originate from the
VZ, migrate into the intermediate zone (IZ), and nally to the molecular (ML) and granule (GL) cell layers
late adjacent and inferior to the NTZ before descending to
their destination (Prekop etal. 2018).
From e13.5, Olig2 is downregulated and subsequent pop-
ulations of GABAergic neurons express Gsx1 (Seto et al.
2014) and Pax2 (Maricich and Herrup 1999; Weisheit etal.
2006). Pax2-positive precursors proliferate within the white
matter through to P15 and migrate radially to sequentially
form various GABAergic interneuron populations: rst the
CN interneurons, then Golgi cells of the granule cell layer,
and nally basket and stellate cells of the molecular layer
(Leto etal. 2006). A growing body of evidence shows that
specication is controlled post-mitotically by factors in the
local microenvironment (Leto et al. 2009; Grimaldi et al.
2009; Zordan et al. 2008), although their identity, and the
contribution, if any, of intrinsic cues are still largely
undened.
16.2 Future Studies will Need toAddress
Fine-Grain Patterning ofDierent
Nuclei
16.1.2 GABAergic Neurons are Derived
fromtheVentricular Zone
Fate-mapping studies indicate that GABAergic CN cells are
derived from Ptf1a-positive precursors in the VZ in two
phases (Hoshino etal. 2005). First, GABAergic neurons that
project long axons from the CN to the inferior olive
(Mugnaini and Oertel 1985; Ruigrok 1997) are born within a
distinct temporal window alongside Purkinje cells (e10.5–
e12.5), both characterized by the expression of Olig2. In synchrony with the glutamatergic projection neurons being
derived from the RL, these nucleo-olivary neurons accumu-
Our current understanding outlines basic principles of CN
development in terms of progenitor zones, temporal patterning, and the function of a few key transcription factors.
Recent studies have illustrated how the discovery of new
molecular and genetic markers has allowed fate mapping of
distinct cell types. Detailed studies of cell organization
within the lateral nucleus have revealed intricate cell arrangements and alignment of projections along a polarized axis
within the nucleus (Chan-Palay 1977). In addition, single
cell and spatial omics analysis have made possible deeper
interrogation of developing cell types, as well as postulate
how conserved cell types may form an archetypal nucleus
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H.-T. Kwok and R. J. T. Wingate
that has duplicated with variation over evolution. This has
shown that while the ventricular zone-derived inhibitory
cells are genetically uniform across nuclei, it is the rhombic
lip derived glutamatergic populations that confer genetic
diversity on the cerebellar nuclei (Kebschull etal. 2020).
How neuroblasts migrate, differentiate, and successfully
form functional circuits are important open questions. The
identity of cues that shape CN circuits will be important targets for future research. This will also help in assessing the
impact of CN dysgenesis on a broad spectrum of cerebellar
disorders that can produce both classical motor symptoms
and an emerging range of cognitive effects in syndromes
such as Autistic Spectrum Disorder and Joubert Syndrome
(Schmahmann 2010; Wang etal. 2014; Holroyd etal. 1991).
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Development ofGlutamatergic
https://t.me/medicina_free
andGABAergic Synapses
MarcoSassoè-Pognetto
17
Abstract
Due to its stereotyped cellular architecture, the cerebel-
lum has always constituted a useful model system for
studying the basic organization and development of syn-
aptic circuits. This chapter describes the current state of
knowledge relating to the development of cerebellar glu-
tamate and GABA synapses and highlights observations
on the molecular and activity-dependent mechanisms that
control the spatial specicity of synaptogenesis.
Keywords
Glutamate synapse · GABA synapse · Synaptogenesis
Synaptic specicity
The cerebellum has a prolonged course of development that
largely extends into postnatal life (Wang and Zoghbi 2001).
This feature, together with the availability of several natural
mutants and of cell-specic genetic tools (Sotelo 2004; Sajan
etal. 2010), makes the cerebellum one of the most accessible
brain regions for studying synaptogenesis in situ.
The cerebellar cortex has a relatively simple organization,
consisting of only a few cell types that integrate two major
inputs (Fig. 17.1). Purkinje cells (PCs), which are
GABAergic, provide the only output of the cerebellar cortex,
sending their axons to the deep cerebellar nuclei (DCN). PCs
receive direct connections from climbing bers (CFs), which
originate from inferior olive neurons, and indirect connections from mossy bers (MFs), which connect to granule cell
dendrites within glomeruli in the granule cell layer (GCL).
The axons of granule cells ascend to the molecular layer
(ML), where they bifurcate and give rise to parallel bers
(PFs), which make synapses with the dendrites of PCs as
well as other cerebellar neurons. Local inhibitory interneurons comprise stellate and basket cells, which modulate PC
output in the ML, and Golgi cells, which provide feedback
and feedforward inhibition to granule cells in the GCL.
In the cerebellar cortex, synaptogenesis is entirely postnatal, although it occurs at rather different rates in different
lobules (Altman 1972a, b, c). In both mice and rats, synapses start to form in the rst postnatal week, and reach
adult densities at the end of the third week (Fig.17.2). The
entire period of synaptogenesis is characterized by a progressive growth of the granular and molecular layers, and a
proliferation of synapses from the bottom upward. Only a
few studies have specically investigated the development
of synaptic connectivity in the deep cerebellar nuclei
(Eisenman etal. 1991; Garin and Escher 2001). These investigations have suggested that synaptogenesis may start in
the nuclei well before the emergence of the rst synapses in
the cerebellar cortex, but the precise pattern remains to be
determined.
M. Sassoè-Pognetto (*)
Department of Neuroscience, C.so Massimo d’Azeglio, Turin, Italy
e-mail: marco.sassoe@unito.it
© 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_17
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