Cerebellar development and disease

doi:10.1016/j.conb.2008.05.010

Current Opinion in Neurobiology

Volume 18, Issue 1, February 2008, Pages 12-19

https://doi.org/10.1016/j.conb.2008.05.010 Get rights and content

The molecular control of cell-type specification within the developing cerebellum as well as the genetic causes of the most common human developmental cerebellar disorders have long remained mysterious. Recent genetic lineage and loss-of-function data from mice have revealed unique and nonoverlapping anatomical origins for GABAergic neurons from ventricular zone precursors and glutamatergic cell from rhombic lip precursors, mirroring distinct origins for these neurotransmitter-specific cell types in the cerebral cortex. Mouse studies elucidating the role of Ptf1a as a cerebellar ventricular zone GABerigic fate switch were actually preceded by the recognition that PTF1A mutations in humans cause cerebellar agenesis, a birth defect of the human cerebellum. Indeed, several genes for congenital human cerebellar malformations have recently been identified, including genes causing Joubert syndrome, Dandy-Walker malformation, and pontocerebellar hypoplasia. These studies have pointed to surprisingly complex roles for transcriptional regulation, mitochondrial function, and neuronal cilia in patterning, homeostasis, and cell proliferation during cerebellar development. Together, mouse and human studies are synergistically advancing our understanding of the developmental mechanisms that generate the uniquely complex mature cerebellum.

Introduction

The basic circuitry of the mature cerebellum has been known for more than 100 years; however, the developmental mechanisms that generate this complexity have only begun to be elucidated much more recently. The study of spontaneous and targeted mutations in mice that cause congenital ataxias has been fundamental to this progress. More recently, the use of powerful new genetic fate-mapping technology in cerebellar mutant mice has driven many of the new molecular insights of cerebellar development. Concurrently, multiple human cerebellar malformations have been delineated because of improvements in neuroimaging and improved classification of these disorders. This has fueled the identification of several disease genes leading to a new molecular classification of these disorders and permitted construction of mouse models to delineate the underlying pathogenesis. Together, mouse and human genetic approaches are synergistically driving significant progress toward an improved understanding of the basic mechanisms of cerebellar development.

Section snippets

Cerebellar morphogenesis

The cerebellum arises from dorsal rhombomere 1 of the anterior hindbrain and is positioned along the anterior/posterior axis of the neural tube by Fgf and Wnt signals from the isthmic organizer located at the midbrain–hindbrain junction [1]. The developing cerebellum is also influenced by the adjacent fourth ventricle roof plate, which secretes Bmp, Wnt, and retinoic acid [2••, 3•] (Figure 1a). Mouse fate-mapping experiments have shown that during early embryogenesis, there is a 90° rotation of

Conclusions

The cerebellum plays crucial roles in sensory integration, motor planning as well higher cognitive processing [71]. Despite its importance, we know surprisingly little about its development. The use of new fate-mapping strategies in mice has helped define unexpected origins for unique cellular populations within the cerebellum. Defining the genetic underpinnings of some of the common causes of cerebellar malformations in humans holds the promise of improving diagnosis and prognostic information

References and recommended reading

Papers of particular interest, published over the period of the review, have been highlighted as:

• of special interest
•• of outstanding interest

References (71)

V. Chizhikov et al.
Development and malformations of the cerebellum in mice
Mol Genet Metab
(2003)
Aldinger K, Elsen G: Ptf1a is a molecular determinant for both glutamatergic and GABAergic neurons in the hindbrain. J...
C. Akazawa et al.
A mammalian helix–loop–helix factor structurally related to the product of Drosophila proneural gene atonal is a positive transcriptional regulator expressed in the developing nervous system
J Biol Chem
(1995)
R. Wingate
Math-Map(ic)s
Neuron
(2005)
R.F. Hevner et al.
Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus
Neurosci Res
(2006)
N. Ben-Arie et al.
Math1 is essential for genesis of cerebellar granule neurons
Nature
(1997)
J. Alder et al.
Embryonic precursor cells from the rhombic lip are specified to a cerebellar granule neuron identity
Neuron
(1996)
B.L. Maria et al.
Clinical features and revised diagnostic criteria in Joubert syndrome
J Child Neurol
(1999)
T. Dixon-Salazar et al.
Mutations in the AHI1 gene, encoding Jouberin, cause Joubert syndrome with cortical polymicrogyria
Am J Hum Genet
(2004)
M.A. Parisi et al.
The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome
Am J Hum Genet
(2004)

M. Delous et al.

The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome

Nat Genet

(2007)

F. Brancati et al.

CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders

Am J Hum Genet

(2007)

D. Huangfu et al.

Cilia and Hedgehog responsiveness in the mouse

Proc Natl Acad Sci U S A

(2005)

J. Aruga

The role of Zic genes in neural development

Mol Cell Neurosci

(2004)

E.E. Govek et al.

The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis

Nat Neurosci

(2004)

H.G. Serra et al.

RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice

Cell

(2006)

T. Sato et al.

How does Fgf signaling from the isthmic organizer induce midbrain and cerebellum development?

Dev Growth Differ

(2004)

V.V. Chizhikov et al.

The roof plate regulates cerebellar cell-type specification and proliferation

Development

(2006)

L.J. Wilson et al.

Retinoic acid is a potential dorsalising signal in the late embryonic chick hindbrain

BMC Dev Biol

(2007)

S.K. Sgaier et al.

Morphogenetic and cellular movements that shape the mouse cerebellum; insights from genetic fate mapping

Neuron

(2005)

A. Louvi et al.

The isthmic neuroepithelium is essential for cerebellar midline fusion

Development

(2003)

M. Hoshino et al.

Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum

Neuron

(2005)

M. Pascual et al.

Cerebellar GABAergic progenitors adopt an external granule cell-like phenotype in the absence of Ptf1a transcription factor expression

Proc Natl Acad Sci U S A

(2007)

N. Ben-Arie et al.

Evolutionary conservation of sequence and expression of the bHLH protein Atonal suggests a conserved role in neurogenesis

Hum Mol Genet

(1996)

S.G. Kalinichenko et al.

Unipolar brush cells — a new type of excitatory interneuron in the cerebellar cortex and cochlear nuclei of the brainstem

Neurosci Behav Physiol

(2005)

V.Y. Wang et al.

Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum

Neuron

(2005)

R. Machold et al.

Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors

Neuron

(2005)

C. Englund et al.

Unipolar brush cells of the cerebellum are produced in the rhombic lip and migrate through developing white matter

J Neurosci

(2006)

A.J. Fink et al.

Development of the deep cerebellar nuclei: transcription factors and cell migration from the rhombic lip

J Neurosci

(2006)

R.P. Machold et al.

Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip

Neural Dev

(2007)

M. Kumar et al.

Pancreas specification: a budding question

Curr Opin Genet Dev

(2003)

G.S. Sellick et al.

Mutations in PTF1A cause pancreatic and cerebellar agenesis

Nat Genet

(2004)

M. Joubert et al.

Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation

Neurology

(1969)

A. Gherman et al.

The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia

Nat Genet

(2006)

R.J. Ferland et al.

Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome

Nat Genet

(2004)

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Little brain, little minds: The big role of the cerebellum in social development
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Seminal work in the 1990’s found alterations in the cerebellum of individuals with social disorders including autism spectrum disorder and schizophrenia. In neurotypical populations, distinct portions of the posterior cerebellum are consistently activated in fMRI studies of social cognition and it has been hypothesized that the cerebellum plays an essential role in social cognition, particularly in theory of mind. Here we review the lesion literature and find that the effect of cerebellar damage on social cognition is strongly linked to the age of insult, with dramatic impairments observed after prenatal insult, strong deficits observed after childhood damage, and mild and inconsistent deficits observed following damage to the adult cerebellum. To explain the developmental gradient, we propose that early in life, the forward model dominates cerebellar computations. The forward model learns and uses errors to help build schemas of our interpersonal worlds. Subsequently, we argue that once these schemas have been built up, the inverse model, which is the foundation of automatic processing, becomes dominant. We provide suggestions for how to test this, and also outline directions for future research.
Differentiation of Purkinje cells from pluripotent stem cells for disease phenotyping in vitro
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The cerebellum is important for regulating motor function and movement coordination, and more recently has been shown to regulate various behavioral functions, including cognition and communication of affection. Degeneration of the cerebellum and loss of Purkinje cells are the main causes for cerebellar ataxia, and dysfunctional Purkinje cells have also been associated in the development of autism. Purkinje cells are the sole output neurons of the cerebellum. Characterization of human Purkinje cell development is important for understanding the causes of cerebellar degeneration and neurodevelopmental disorders associated with Purkinje cell deficits.
In this chapter, we describe a patterning-based differentiation protocol for the development of Purkinje cells from induced pluripotent stem cells (iPSCs) for disease phenotyping of cerebellar disorders. First, we describe the development of the hindbrain region and the cerebellum during embryogenesis, and then we introduce characterization of the specific neuronal cell types in the cerebellum. We will focus on the establishment of cell culture protocols for derivation of Purkinje cells from pluripotent stem cells with two-dimensional co-culture platforms and three-dimensional brain organoid methods. In addition, we will introduce two neurological disorders, cerebellar ataxia and tuberous sclerosis complex, which have profound deficits in the development and degeneration of Purkinje cells. We will describe disease phenotyping of these disorders with mouse models and patient-specific iPSC-derived Purkinje cell culture models. Finally, we will focus on future avenues of disease modeling and development of patient-specific drug screening platforms with iPSC-derived Purkinje cells.
Intrauterine growth restriction compromises cerebellar development by affecting radial migration of granule cells via the JamC/Pard3a molecular pathway
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Intrauterine growth restriction (IUGR) affects ~10% of human pregnancies, results in infants born small for gestational age (SGA), and is associated with motor and cognitive deficits. Human studies suggest that some deficits in SGA patients originate in the cerebellum, a major motor-coordination and cognitive center, but the underlying mechanisms remain unknown. To identify the cerebellar developmental program affected by IUGR, we analyzed the pig as a translational animal model in which some fetuses spontaneously develop IUGR due to early-onset chronic placental insufficiency. Similar to humans, SGA pigs revealed small cerebella, which contained fewer mature granule cells (GCs) in the internal granule cell layer (IGL). Surprisingly, newborn SGA pigs had increased proliferation of GC precursors in the external granule cell layer (EGL), which was associated with an increased density of Purkinje cells, known to non-autonomously promote the proliferation of GCs. However, the GCs of SGA pigs did not properly initiate exit from the EGL to IGL, which was associated with a decreased density of guiding Bergmann glial fibers, reduced expression of pro-migratory genes Pard3a, JamC and Sema6a, and increased apoptosis. While proliferation spontaneously normalized during postnatal development, accumulation of pre-migratory GCs and apoptosis in the EGL were long-lasting consequences of IUGR. Using organotypic cerebellar slice cultures, we showed that normalizing expression of Pard3a and JamC, which operate in the same molecular pathway in GCs, was sufficient to rescue both migratory and, at a later time point, apoptotic defects of IUGR. Thus, a decreased exit of GCs from the EGL, due to disrupted Pard3a/JamC radial migration initiation pathway, is a major mechanism of IUGR-related cerebellar pathology.
DVL mutations identified from human neural tube defects and Dandy-Walker malformation obstruct the Wnt signaling pathway
2020, Journal of Genetics and Genomics
Wnt signaling pathways, including the canonical Wnt/β-catenin pathway, planar cell polarity pathway, and Wnt/Ca²⁺ signaling pathway, play important roles in neural development during embryonic stages. The DVL genes encode the hub proteins for Wnt signaling pathways. The mutations in DVL2 and DVL3 were identified from patients with neural tube defects (NTDs), but their functions in the pathogenesis of human neural diseases remain elusive. Here, we sequenced the coding regions of three DVL genes in 176 stillborn or miscarried fetuses with NTDs or Dandy-Walker malformation (DWM) and 480 adult controls from a Han Chinese population. Four rare mutations were identified: DVL1 p.R558H, DVL1 p.R606C, DVL2 p.R633W, and DVL3 p.R222Q. To assess the effect of these mutations on NTDs and DWM, various functional analyses such as luciferase reporter assay, stress fiber formation, and in vivo teratogenic assay were performed. The results showed that the DVL2 p.R633W mutation destabilized DVL2 protein and upregulated activities for all three Wnt signalings (Wnt/β-catenin signaling, Wnt/planar cell polarity signaling, and Wnt/Ca²⁺ signaling) in mammalian cells. In contrast, DVL1 mutants (DVL1 p.R558H and DVL1 p.R606C) decreased canonical Wnt/β-catenin signaling but increased the activity of Wnt/Ca²⁺ signaling, and DVL3 p.R222Q only decreased the activity of Wnt/Ca²⁺ signaling. We also found that only the DVL2 p.R633W mutant displayed more severe teratogenicity in zebrafish embryos than wild-type DVL2. Our study demonstrates that these four rare DVL mutations, especially DVL2 p.R633W, may contribute to human neural diseases such as NTDs and DWM by obstructing Wnt signaling pathways.
Early-life stress increases granule cell density in the cerebellum of male rats
2019, Brain Research
Citation Excerpt :
These characteristics have been termed as ‘cerebellar cognitive affective syndrome.’ Additionally, patients with major depression presented a lower activation of the cerebellum and the thalamus after an emotional challenge (Konarski et al., 2005; Millen and Gleeson, 2008). In conclusion, we showed that the cerebellum is a structure that is vulnerable to early-life stress.
In rodents, daily maternal separation for 180 min (MS180) during the first weeks of life affects hippocampal granule cell neurogenesis. Development of the cerebellum granule cell layer also occurs during the first weeks of life. However, whether MS180 affects this neurogenic niche remains unknown. To study this, we evaluated the immediate and long term effect of MS180 on granule cell survival within the cerebellum. Pups were injected twice at an 8-hour interval at PND (postnatal day) 5 with bromodeoxyuridine (BrdU, 50 mg/kg) and were sacrificed ten days later (PND15) or allowed to survive into adulthood (PND60). We observed a higher density of BrdU-positive cells in the cerebellar foliae (p < 0.05) of MS180 pups at PND15. This increase was also observed in both, cerebellar foliae and fissures (p < 0.05) at PND60. Triple immunofluorescence staining against BrdU, NeuN (a marker of mature neurons), and GFAP (a marker of mature glia), revealed that BrdU + cells labeled at PND5 co-localized with NeuN but not with GFAP, indicating that they were mature neurons. MS180 did not affect baseline corticosterone levels at PND15 but significantly increased adult corticosterone levels (p < 0.05). In conclusion, MS180 increased cell survival in the granular layer of cerebellar foliae and fissures and resulted in further integration of the cells into adult circuits. These effects occurred without early alterations of basal corticosterone by MS180. Our results indicate that early-life stress induces a permanent increase in cerebellar neurogenesis.
Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis
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Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predisposed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.

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Cerebellar development and disease

Introduction

Section snippets

Cerebellar morphogenesis

Conclusions

References and recommended reading

Mol Genet Metab

J Biol Chem

Neuron

Neurosci Res

Nature

Neuron

J Child Neurol

Am J Hum Genet

Am J Hum Genet

Nat Genet

Am J Hum Genet

Proc Natl Acad Sci U S A

Mol Cell Neurosci

Nat Neurosci

Cell

How does Fgf signaling from the isthmic organizer induce midbrain and cerebellum development?

Dev Growth Differ

The roof plate regulates cerebellar cell-type specification and proliferation

Development

Retinoic acid is a potential dorsalising signal in the late embryonic chick hindbrain

BMC Dev Biol

Morphogenetic and cellular movements that shape the mouse cerebellum; insights from genetic fate mapping

Neuron

The isthmic neuroepithelium is essential for cerebellar midline fusion

Development

Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum

Neuron

Cerebellar GABAergic progenitors adopt an external granule cell-like phenotype in the absence of Ptf1a transcription factor expression

Proc Natl Acad Sci U S A

Evolutionary conservation of sequence and expression of the bHLH protein Atonal suggests a conserved role in neurogenesis

Hum Mol Genet

Unipolar brush cells — a new type of excitatory interneuron in the cerebellar cortex and cochlear nuclei of the brainstem

Neurosci Behav Physiol

Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum

Neuron

Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors

Neuron

Unipolar brush cells of the cerebellum are produced in the rhombic lip and migrate through developing white matter

J Neurosci

Development of the deep cerebellar nuclei: transcription factors and cell migration from the rhombic lip

J Neurosci

Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip

Neural Dev

Pancreas specification: a budding question

Curr Opin Genet Dev

Mutations in PTF1A cause pancreatic and cerebellar agenesis

Nat Genet

Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation

Neurology

The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia

Nat Genet

Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome

Nat Genet