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Developmental origins of the mouse cerebellum and the role of isthmic gene expression in patterning the vermis. (A) Schematic representation of a mid-gestation embryo showing the location of derivatives of rhombomere 1. The ventricular layer (green) and rhombic lip (brown) of dorsal rhombomere 1 give rise to all GABA-ergic and glutamatergic cells of the cerebellum, respectively. (B) In a dorsal (posterior) view, the adult cerebellum is characterized by a central (darker shaded) vermis running anterior (ant) to posterior (pos). A uniform layering of cell types can be found throughout the vermis and more lateral hemispheres (shown in schematic parasagittal section), with GABA-ergic and glutamatergic differentially distributed in a later-specific manner: the molecular layer is largely reserved for the interaction of Purkinje cell dendrites and granule cell axons with sparse basket and stellate inhibitory interneurons. The Purkinje cells layer separates the molecular layer from an internal granule cell layer that contains a population of inhibitory Golgi cells. Deep cerebellar nuclei (GABA-ergic and glutamatergic neurons) lie within the white matter. (C) Schematic diagram showing the location of the isthmus organizer at the midbrain/hindbrain boundary with respect to the fourth ventricle roof plate (rp) and the expression domains of Wnt1 (purple) and Fgf8 (blue). (D) Dorsal schematic view of the isthmus region showing with darker shading the approximate region where progenitors of the cerebellar vermis reside, as based on inducible fate-mapping studies (Sgaier et al., 2005). The translation of this dorsal rhombomere 1 territory into adult vermis is shown inset. (E) Altered morphology of the isthmic region and reduced cerebellar size in a hypomorph with an altered function of the isthmic organizer due to diminished FGF signaling. Loss of vermis progenitors is concomitant with the expansion of the roof plate (adapted from Basson et al., 2008). The consequences for vermal morphogenesis in the adult are shown inset.
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Over the last 60 years, the spotlight of research has periodically returned to the cerebellum as new techniques and insights have emerged. Because of its simple homogeneous structure, limited diversity of cell types and characteristic behavioral pathologies, the cerebellum is a natural home for studies of cell specification, patterning, and neurona...
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Citations
... Several studies have brought to the fore the essential contribution of the cerebellum to the regulation of neurocognitive functions, directed by specific brain regions with which the cerebellum is reciprocally linked, such as speech, cognitive processing and emotional regulation Basson & Wingate, 2013;Becker & Stoodley, 2013;Kasselimis et al., 2008;Sveljio et al., 2014;. With its uniform cortical architecture, the cerebellum's connectional specificity allows it to modulate a wide array of behaviors . ...
A large body of literature, including preclinical histopathology, genetic and neuroimaging studies has established the involvement of the cerebellar circuits in the physiopathology of Autism Spectrum Disorder (ASD). The aim of the present study was to assess at a behavioral level the cerebellar function of preschool children aged 4 to 6 years old with ASD, in comparison to a group of age-matched typically developing (TD) children. Seven clinical tests were administered to measure performance into three main areas of cerebellar function: maintenance of posture, hypotonia (reduced muscle tone), and complex movements. Our results showed that children with ASD performed significantly lower in 6 out of 7 cerebellar tests compared to TD children. These findings indicate that cerebellar-dependent motor behaviours are compromised in preschool children with a diagnosis of ASD. Our findings are
consistent with previous studies supporting a general cerebellar dysfunction in children with ASD and indicate that these impairments can emerge and be detected as early as at the preschool period of development.
... It was noted a decade ago that the cerebellum plays an important role in cognitive processes and social behaviour (Becker & Stoodley, 2013;Basson & Wingate, 2013). Cerebellum aberrant development has been observed in individuals with ASD (Scott et al., 2009;Sathyanesan et al., 2019). ...
... Cerebellum aberrant development has been observed in individuals with ASD (Scott et al., 2009;Sathyanesan et al., 2019). Furthermore, prenatal administration of VPA in mice models has resulted in cerebellar developmental defects and an impaired gene expression profile (Becker & Stoodley, 2013;Basson & Wingate, 2013;Guerra et al., 2023). In particular, Wang and colleagues (2018) observed premature migration of granular cell precursors and a decrease in the number of Purkinje cells (PC) in the cerebellar cortex, which correlates with their impaired synaptic functionality. ...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which genetic and environmental factors interact in its development. Research suggests that the contactin associated protein 2 (CNTNAP2) gene may play a role in ASD pathophysiology, yet more studies involving human participants and animal models of autism are needed. One such model may be the use of prenatal valproic acid (VPA) model to induce autism-like behaviors in offspring rats. The aim of this study was twofold: (1) to examine the association of the CNTNAP2 gene rs2710102 variant with ASD in children; and (2) to examine the effect of prenatal exposure to VPA on Cntnap2 gene expression in the rat brain. The study included 167 children of European ancestry-81 diagnosed with ASD (20 girls, 61 boys; age 4.9 ± 1.4 years) and 86 controls (44 girls, 42 boys; 5.1 ± 1.2 years). In vivo experiments were conducted in 80 rats (40 with the VPA model of autism), with Cntnap2 gene expression analysis in the amygdala, hippocampus, prefrontal cortex, and cere-bellum. Results demonstrated that the frequency of the CNTNAP2 gene rs2710102 GG genotype was significantly higher in children with ASD when compared with controls (33.3 vs 19.8%; OR=2.03, 95%CI [1.004, 4.102], p = 0.035), although, potentially due to bias in cohort selection, in the ASD children this polymorphism did not meet Hardy-Weinberg expectations (χ 2 =5.40, p = 0.02). In addition, Cntnap2 gene expression was significantly lower (p < 0.01) in the amygdala and hippocampus of VPA rats when compared with controls, regardless of sex. These results support previous research and provide evidence for the CNTNAP2 gene as a risk factor for ASD.
... This case posed numerous diagnostic and prognostic challenges as an 'n of one' case. The original challenge at the time of fetal presentation was determining which cerebellar hemisphere was abnormal, as unilateral cerebellar hyperplasia is an atypical explanation for asymmetric cerebellar development compared to unilateral cerebellar hypoplasia [19], which can result from direct injury, supratentorial injury resulting in crossed cerebellar diaschisis, and genetic etiologies [20], as well as PHACE syndrome [21], which has no identified genetic cause at this time. Much greater challenges were encountered next, including what the abnormalities might represent, what the potential underlying cause was, and most importantly for the family, what the potential neurological implications of these uncertain findings might be. ...
Fetal neurology encompasses the full spectrum of neonatal and child neurology presentations, with complex additional layers of diagnostic and prognostic challenges unique to the specific prenatal consultation. Diverse genetic and acquired etiologies with a range of potential outcomes may be encountered. Three clinical case presentations are discussed that highlight how postnatal phenotyping and longitudinal follow-up are essential to address the uncertainties that arise in utero, after birth, and in childhood, as well as to provide continuity of care. Key messages • Diverse neurologic conditions may present in utero with a wide range of potential outcomes. • Prenatal prognostic counseling regarding neurodevelopmental outcome is frequently uncertain, even when a diagnosis is confirmed. • Postnatal phenotyping and longitudinal follow-up are essential to inform the diagnosis and prognosis over time, as well as to provide continuity of care. • Focusing on the developing child, their progress, and the importance of developmental enrichment and early intervention services, can help parents/caregivers navigate the unknowns after delivery.
... The cerebellum is classically known to play a role in motor control, and it is now considered to contribute to many cognitive functions via connections with the cerebral cortex 2,3 . Injuries or diseases affecting the cerebellum have usually been linked to spinocerebellar ataxia, congenital cerebellar hypoplasia, intellectual disability, autism spectrum disorder (ASD), medulloblastoma, etc [4][5][6][7][8] . ...
Human cerebellar development is orchestrated by molecular regulatory networks to achieve cytoarchitecture and coordinate motor and cognitive functions. Here, we combined single-cell transcriptomics, spatial transcriptomics and single cell chromatin accessibility states to systematically depict an integrative spatiotemporal landscape of human fetal cerebellar development. We revealed that combinations of transcription factors and cis-regulatory elements (CREs) play roles in governing progenitor differentiation and cell fate determination along trajectories in a hierarchical manner, providing a gene expression regulatory map of cell fate and spatial information for these cells. We also illustrated that granule cells located in different regions of the cerebellar cortex showed distinct molecular signatures regulated by different signals during development. Finally, we mapped single-nucleotide polymorphisms (SNPs) of disorders related to cerebellar dysfunction and discovered that several disorder-associated genes showed spatiotemporal and cell type-specific expression patterns only in humans, indicating the cellular basis and possible mechanisms of the pathogenesis of neuropsychiatric disorders.
... For example, in both the cerebellum and neocortex, neuronal lamina are created by sequential rounds of cell division by neuronal progenitors followed by progressive migration of newly generated neurons into distinct layers (Angevine and Sidman, 1961;Altman, 1972). Aberrant neuronal proliferation can alter the size of the neocortex and cerebellum causing disorders such as microcephaly and cerebellar hypoplasia (Basson and Wingate, 2013;Accogli et al., 2021). Similarly, deficits in neuronal migration can disrupt lamination and cause heterotopia in these regions (Bahi-Buisson and Guerrini, 2013;Parrini et al., 2016). ...
Brain malformations cause cognitive disability and seizures in both human and animal models. Highly laminated structures such as the neocortex and cerebellum are vulnerable to malformation, affecting lamination and neuronal connectivity as well as causing heterotopia. The objective of the present study was to determine if sporadic neocortical and/or cerebellar malformations in C57BL/6J mice are correlated with reduced seizure threshold. The inhaled chemi-convulsant flurothyl was used to induce generalized, tonic-clonic seizures in male and female C57BL/6J mice, and the time to seizure onset was recorded as a functional correlate of brain excitability changes. Following seizures, mice were euthanized, and brains were extracted for histology. Cryosections of the neocortex and cerebellar vermis were stained and examined for the presence of molecular layer heterotopia as previously described in C57BL/6J mice. Over 60% of mice had neocortical and/or cerebellar heterotopia. No sex differences were observed in the prevalence of malformations. Significantly reduced seizure onset time was observed dependent on sex and the type of malformation present. These results raise important questions regarding the presence of malformations in C57BL/6J mice used in the study of brain development, epilepsy, and many other diseases of the nervous system.
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Dandy-Walker Syndrome (DWS) is a rare congenital neurological condition characterized by cerebellar and posterior fossa malformations, often presenting a variable clinical spectrum. Common complications include hydrocephalus, necessitating interventions like ventriculoperitoneal (VP) shunts, and endoscopic third ventriculostomy (ETV). We describe the case of a five-month-old infant conceived through in vitro fertilization (IVF), initially presenting with cold-like symptoms, later diagnosed with DWS. The patient underwent VP shunt placement for hydrocephalus management, with subsequent complications requiring shunt revisions and ETV. Vigilant monitoring and timely interventions were crucial for a favorable outcome, highlighting the challenges in diagnosing and managing DWS and the importance of tailored treatment strategies.
... Cortical organoids at around day 50 coincide with the post-conception week (PCW) 14-16 in humans [71]. Impaired region-specific NPC proliferation and neurogenesis have been closely linked to primary microcephaly and vermis/cerebellar hypoplasia [72,73]. We tried the protocol of cerebellum organoids described by the Sasai group [74]. ...
Background
Oxidation Resistance 1 (OXR1) gene is a highly conserved gene of the TLDc domain-containing family. OXR1 is involved in fundamental biological and cellular processes, including DNA damage response, antioxidant pathways, cell cycle, neuronal protection, and arginine methylation. In 2019, five patients from three families carrying four biallelic loss-of-function variants in OXR1 were reported to be associated with cerebellar atrophy. However, the impact of OXR1 on cellular functions and molecular mechanisms in the human brain is largely unknown. Notably, no human disease models are available to explore the pathological impact of OXR1 deficiency.
Results
We report a novel loss-of-function mutation in the TLDc domain of the human OXR1 gene, resulting in early-onset epilepsy, developmental delay, cognitive disabilities, and cerebellar atrophy. Patient lymphoblasts show impaired cell survival, proliferation, and hypersensitivity to oxidative stress. These phenotypes are rescued by TLDc domain replacement. We generate patient-derived induced pluripotent stem cells (iPSCs) revealing impaired neural differentiation along with dysregulation of genes essential for neurodevelopment. We identify that OXR1 influences histone arginine methylation by activating protein arginine methyltransferases (PRMTs), suggesting OXR1-dependent mechanisms regulating gene expression during neurodevelopment. We model the function of OXR1 in early human brain development using patient-derived brain organoids revealing that OXR1 contributes to the spatial–temporal regulation of histone arginine methylation in specific brain regions.
Conclusions
This study provides new insights into pathological features and molecular underpinnings associated with OXR1 deficiency in patients.
... The cerebellum is a highly folded and neuron-dense structure that has been classically involved in the control of motor functions. However, several studies have now clearly shown that the cerebellum is also involved in high order cognitive functions and social behaviours [22][23][24]. The posterior vermis, and particularly lobule VI and Crus I and II in lobule VII, display significant differences in ASD patients [25,26]. ...
Autism spectrum disorder (ASD) includes a set of highly heritable neurodevelopmental syndromes characterized by social and communication impairment, repetitive behaviour, and intellectual disability. Although mutations in multiple genes have been associated to ASD, most patients lack detectable genetic alterations. For this reason, environmental factors are commonly thought to also contribute to ASD aetiology. Transcriptome analyses have revealed that autistic brains possess distinct gene expression signatures, whose elucidation can provide insights about the mechanisms underlying the effects of ASD-causing genetic and environmental factors. Herein, we have identified a coordinated and temporally regulated programme of gene expression in the post-natal development of cerebellum, a brain area whose defects are strongly associated with ASD. Notably, this cerebellar developmental programme is significantly enriched in ASD-linked genes. Clustering analyses highlighted six different patterns of gene expression modulated during cerebellar development, with most of them being enriched in functional processes that are frequently dysregulated in ASD. By using the valproic acid mouse model of ASD, we found that ASD-linked genes are dysregulated in the developing cerebellum of ASD-like mice, a defect that correlates with impaired social behaviour and altered cerebellar cortical morphology. Moreover, changes in transcript levels were reflected in aberrant protein expression, indicating the functional relevance of these alterations. Thus, our work uncovers a complex ASD-related transcriptional programme regulated during cerebellar development and highlight genes whose expression is dysregulated in this brain area of an ASD mouse model.
... The cerebellar primordium emerges at approximately 28 days postfertilization in humans (embryonic day 7-8 in the mouse) as a neuroepithelial swelling of the rostral lip of the fourth ventricle, which is part of the alar plate of the metencephalon (rhombomere-1) [31][32][33]. Therefore, any developmental dysregulation that targets the rhombomere-1 causes failure to specify the anterior hindbrain and results in cerebellar aplasia/hypoplasia because of defects in dorsal patterning mechanisms [34][35][36]. Cerebellar hypoplasia is a heterogeneous group of disorders that was first reported by Crouzon in 1929. ...
... The zinc finger protein of the cerebellum 1 (ZIC1) and zinc finger protein of the cerebellum 4 (ZIC4) genes on 3q24 [50] and FOXCI are candidate genes, and DWM results when they are deleted [51]. It is suggested that Zic1 and Zic4 are required for the full responsiveness of granule cell precursors (GCPs) to sonic hedgehog (SHH), but the role of the Foxc1 is not understood [36]. ...
... DWM is characterized by partial or complete agenesis of the vermis, upward rotation of the vermis, and an enlarged posterior cranial fossa [1,36,52,53]. It is also characterized by cystic dilation of the fourth ventricle into the posterior cranial fossa. ...
Inherited cerebellar malformations cause lifelong disability and are not well studied in the newborns because there is a lack of appropriate clinical examination tools. Recently, inherited cerebellar malformations have been investigated using emerging advanced neuroimaging technologies such as magnetic resonance imaging (MRI), which has revealed many developmental disorders of the cerebellum. These malformations cause impairments that affect motor and nonmotor functions. Cerebellar hypoplasia (CH), cerebellar dysplasia (CD), Dandy–Walker malformation (DWM), Joubert syndrome and related disorders (JSRDs), pontocerebellar hypoplasia (PCH), rhombencephalosynapsis (RES), lissencephaly with cerebellar hypoplasia (LCH), and Lhermitte–Duclos disease (LDD) are examples of cerebellar malformations which this chapter will focus on using characteristic symptoms and signs. The current approaches for evaluation of the affected patients, differential diagnosis, and management of the malformations will be discussed.
... 76 Moreover, in addition to its well-known role on movement, the cerebellum was shown to be involved in regulation of nonmotor functions such as cognition, learning, attention, and even emotional-related behavior. 77,78 Previous studies identified the anatomical bases for this functional connectivity in the projections between primary motor cortex and dorsolateral prefrontal cortex to cerebellum via the dentate nucleus and modulated by Purkinje cells. 79 A "cerebellar cognitive affective syndrome" described the range of behavioral alterations associated to cerebellar lesions and encompassed abnormal executive functions, spatial recognition, verbal skills, and social interactiveness. ...
Joubert syndrome (JS) is a rare inherited disorder of central nervous system with neonatal/infantile onset, mainly affecting cerebellum and brainstem, and clinically characterized by agenesis or dysgenesis of the cerebellar vermis with accompanying brainstem malformations. More than 20 disease-causing genes have been associated with JS but a clear genotype–phenotype correlation has not been assessed yet. Diagnosis is usually confirmed by detection of the JS neuroradiological hallmark, the molar tooth sign. Patients with JS typically present with neurological manifestations, moreover, a heterogeneous spectrum of multisystemic anomalies may be observed. Signs and symptoms onset varies according to the age range and clinical diagnosis might become complicated. Moreover, specific neurodevelopmental disorders can be associated with JS such as autism spectrum disorders, attention deficit with hyperactivity, and a wide range of behavioral disturbances. Here, we examined the main neurological and neurodevelopmental features of JS according to an age-dependent mode of presentation. Furthermore, differential diagnosis with other neurological syndromes was closely reviewed.
