Talk:Neural - Cerebellum Development
Fetal Growth Restriction Alters Cerebellar Development in Fetal and Neonatal Sheep
Front Physiol. 2019 May 22;10:560. doi: 10.3389/fphys.2019.00560. eCollection 2019.
Yawno T1,2, Sutherland AE1, Pham Y1, Castillo-Melendez M1, Jenkin G1,2, Miller SL1,2.
Fetal growth restriction (FGR) complicates 5-10% of pregnancies and is associated with increased risks of perinatal morbidity and mortality. The development of cerebellar neuropathology in utero, in response to chronic fetal hypoxia, and over the period of high risk for preterm birth, has not been previously studied. Therefore, the objective of this study was to examine the effects of FGR induced by placental insufficiency on cerebellar development at three timepoints in ovine fetal and neonatal development: (1) 115 days gestational age (d GA), (2) 124 d GA, and (3) 1-day-old postnatal age. We induced FGR via single umbilical artery ligation (SUAL) at ~105 d GA in fetal sheep, term is ~147 d GA. Animals were sacrificed at 115 d GA, 124 d GA, and 1-day-old postnatal age; fetuses and lambs were weighed and the cerebellum collected for histopathology. FGR lambs demonstrated neuropathology within the cerebellum after birth, with a significant, ~18% decrease in the number of granule cell bodies (NeuN+ immunoreactivity) within the internal granular layer (IGL) and an ~80% reduction in neuronal extension and branching (MAP+ immunoreactivity) within the molecular layer (ML). Oxidative stress (8-OHdG+ immunoreactivity) was significantly higher in FGR lambs within the ML and the white matter (WM) compared to control lambs. The structural integrity of neurons was already aberrant in the FGR cerebellum at 115 d GA, and by 124 d GA, inflammatory cells (Iba-1+ immunoreactivity) were significantly upregulated and the blood-brain barrier (BBB) was compromised (Pearls, albumin, and GFAP+ immunoreactivity). We confirm that cerebellar injuries develop antenatally in FGR, and therefore, interventions to prevent long-term motor and coordination deficits should be implemented either antenatally or perinatally, thereby targeting neuroinflammatory and oxidative stress pathways. KEYWORDS: blood-brain barrier; brain injury; cerebellum; fetal growth restriction; fetal sheep; preterm; term PMID: 31191328 PMCID: PMC6539217 DOI: 10.3389/fphys.2019.00560
Historic notes on anatomic, physiologic, and clinical research on the cerebellum
Voogd J1, Koehler PJ2. Author information Abstract This chapter is concerned with ideas on the function, structure, and pathology that shaped our present knowledge of the cerebellum. One of the main themes in its early history is its localization subtentorially, leading to misattributions due to clinical observations in trauma and lesion experiments that caused collateral damage to the brainstem. Improvement of techniques led to the insight that it plays a role in movement control (Rolando) or coordination (Flourens). Purkinje initiated the histology of the cerebellar cortex in 1837. Luciani's experiments in 1891 led him to conclude that the cerebellum has a tonic facilitating effect on central structures. Cajal identified the elements of the cortex and their circuitry (1888-1891). The inhibitory nature of the interneurons and the Purkinje cells, and the excitatory connections of the mossy and climbing afferents and the granule cells were established much later by Eccles and Ito. A functional localization for the coordinating action of the cerebellum of the motor system, based on local expansion of the folial chains, was devised by Bolk in 1906. Babinski and Holmes contributed to anatomoclinical insights. Magnus and coworkers showed the cerebellum does not play an essential role in body posture. The heterogeneity of the Purkinje cells with respect to their connections and histochemistry found its expression in the zonal organization of the cerebellar cortex. The roots of modern developments, like cerebellar learning and its involvement in cognition and emotion, can be traced to the theories of Marr and Albus and the pioneering work of the Leiners and Dow. KEYWORDS: Purkinje cells; anatomy; cerebellar learning; cerebellum; cognition; coordination of movements; emotion; history of medicine; history of neuroscience; mental skills PMID: 29903448 DOI: 10.1016/B978-0-444-63956-1.00001-1
The modular architecture and neurochemical patterns in the cerebellar cortex
J Chem Neuroanat. 2018 May 15;92:16-24. doi: 10.1016/j.jchemneu.2018.05.001.
Kalinichenko SG1, Pushchin II2.
Abstract The review deals with topical issues of the neuronal arrangement underlying basic cerebellar functions. The cerebellum and its auxiliary structures contain several hundreds of modules (so called "microzones"). Each module receives the corticopetal input specific for the lobule it belongs to and forms the topographic projection. The precision of the major input-output signal flow in the cerebellar cortex is provided by a pronounced stratification of its synaptic zones of a various origin and regular topography of its afferent connections, interneurons, and efferent neurons. There is a nice match between the anatomical and functional coordinates of the modules, whose spatial boundaries are determined by the spread of afferent excitation and local interneuron connections. The dynamic characteristics of the modules are analyzed by the example of the formation of the nitrergic neuron ensembles and cerebellar projections of corticopetal fibers. The authors discuss the cerebellar blood flow and its relation to the activity of NO/GABAergic Lugaro cells and other interneurons in the cerebellar cortex. A generalized scheme of intra- and intermodular communication is proposed. KEYWORDS: Blood flow regulation; Corticonuclear cerebellar microcomplex; Interneuron integration models; Modular microcircuits; Neurochemical diversity PMID: 29753860 DOI: 10.1016/j.jchemneu.2018.05.001
Bergmann glial Sonic hedgehog signaling activity is required for proper cerebellar cortical expansion and architecture
Dev Biol. 2018 Aug 15;440(2):152-166. doi: 10.1016/j.ydbio.2018.05.015. Epub 2018 May 21.
Cheng FY1, Fleming JT1, Chiang C2. Author information Abstract Neuronal-glial relationships play a critical role in the maintenance of central nervous system architecture and neuronal specification. A deeper understanding of these relationships can elucidate cellular cross-talk capable of sustaining proper development of neural tissues. In the cerebellum, cerebellar granule neuron precursors (CGNPs) proliferate in response to Purkinje neuron-derived Sonic hedgehog (Shh) before ultimately exiting the cell cycle and migrating radially along Bergmann glial fibers. However, the function of Bergmann glia in CGNP proliferation remains not well defined. Interestingly, the Hh pathway is also activated in Bergmann glia, but the role of Shh signaling in these cells is unknown. In this study, we show that specific ablation of Shh signaling using the tamoxifen-inducible TNCYFP-CreER line to eliminate Shh pathway activator Smoothened in Bergmann glia is sufficient to cause severe cerebellar hypoplasia and a significant reduction in CGNP proliferation. TNCYFP-CreER; SmoF/- (SmoCKO) mice demonstrate an obvious reduction in cerebellar size within two days of ablation of Shh signaling. Mutant cerebella have severely reduced proliferation and increased differentiation of CGNPs due to a significant decrease in Shh activity and concomitant activation of Wnt signaling in SmoCKO CGNPs, suggesting that this pathway is involved in cross-talk with the Shh pathway in regulating CGNP proliferation. In addition, Purkinje cells are ectopically located, their dendrites stunted, and the Bergmann glial network disorganized. Collectively, these data demonstrate a previously unappreciated role for Bergmann glial Shh signaling activity in the proliferation of CGNPs and proper maintenance of cerebellar architecture. KEYWORDS: Bergmann glia; Cerebellum; Neuronal-glial relationships; Sonic hedgehog PMID: 29792854 PMCID: PMC6014626 [Available on 2019-08-15] DOI: 10.1016/j.ydbio.2018.05.015
Embryology of the Craniocervical Junction and Posterior Cranial Fossa Part II: Embryogenesis of the hindbrain
Clin Anat. 2018 Jan 18. doi: 10.1002/ca.23048.
Shoja MM1, Jensen CJ2, Ramdhan R2, Chern J3, Oakes WJ4, Tubbs RS3. Author information Abstract Although pathology of the hindbrain and its derivatives can have life altering effects on a patient, a comprehensive review on its embryology is difficult to find in the peer-reviewed medical literature. Therefore, this review paper, using standard search engines, seemed timely. The embryology of the hindbrain is complex and relies on a unique timing of various neurovascular and bony elements. Derailment of these developmental processes can lead to a wide range of malformations such as the Chiari malformations. Therefore, a good working knowledge of this embryology as outlined in this review of the hindbrain is important for those treating patients with involvement of this region of the central nervous system. This article is protected by copyright. All rights reserved. KEYWORDS: Chiari; anatomy; brain; brain stem; cerebellum; genetics; malformation; nervous system PMID: 29344994 DOI: 10.1002/ca.23048
Migration of Interneuron Precursors in the Nascent Cerebellar Cortex
Cerebellum. 2017 Nov 17. doi: 10.1007/s12311-017-0900-7. [Epub ahead of print]
Wefers AK1,2,3, Haberlandt C2, Surchev L1,4, Steinhäuser C2, Jabs R2, Schilling K5.
The cerebellum arguably constitutes one of the best characterized central nervous circuits, and its structure, cellular function, and histogenesis have been described in exceptional quantitative detail. A notable exception to this is the development of its inhibitory interneurons, and in particular the extensive migrations of future basket and stellate cells. Here, we used acute slices from 8-day-old mice to assess the migration of Pax2-EGFP-tagged precursors of these cells en route to the molecular layer during their transit through the nascent cerebellar cortex. We document that movement of these cells is highly directed. Their speed and directional persistence are larger in the nascent granule cell layer than in the molecular layer. And they migrate periodically, with periods of effective, directed translocation separated by bouts of rather local movement. Finally, we document that the arrangement of these cells in the adult molecular layer is characterized by clustering. These data are discussed with a focus on potential generative mechanisms for the developmental pattern observed. KEYWORDS: Cell migration; Cerebellum; Development; Inhibitory interneuron; Mouse; Pax2 PMID: 29149443 DOI: 10.1007/s12311-017-0900-7
Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndrome
Nat Cell Biol. 2017 Oct;19(10):1178-1188. doi: 10.1038/ncb3599. Epub 2017 Aug 28.
Shi X1, Garcia G 3rd2,3, Van De Weghe JC4, McGorty R1, Pazour GJ5, Doherty D4, Huang B1,2,6, Reiter JF2,3.
Ciliopathies, including nephronophthisis (NPHP), Meckel syndrome (MKS) and Joubert syndrome (JBTS), can be caused by mutations affecting components of the transition zone, a domain near the base of the cilium that controls the protein composition of its membrane. We defined the three-dimensional arrangement of key proteins in the transition zone using two-colour stochastic optical reconstruction microscopy (STORM). NPHP and MKS complex components form nested rings comprised of nine-fold doublets. JBTS-associated mutations in RPGRIP1L or TCTN2 displace certain transition-zone proteins. Diverse ciliary proteins accumulate at the transition zone in wild-type cells, suggesting that the transition zone is a waypoint for proteins entering and exiting the cilium. JBTS-associated mutations in RPGRIP1L disrupt SMO accumulation at the transition zone and the ciliary localization of SMO. We propose that the disruption of transition-zone architecture in JBTS leads to a failure of SMO to accumulate at the transition zone and cilium, disrupting developmental signalling in JBTS.
PMID: 28846093 DOI: 10.1038/ncb3599
Pre- and Postnatal Neuroimaging of Congenital Cerebellar Abnormalities
Cerebellum. 2016 Feb;15(1):5-9. doi: 10.1007/s12311-015-0699-z.
Poretti A1,2, Boltshauser E3, Huisman TA4.
The human cerebellum has a protracted development that makes it vulnerable to a broad spectrum of developmental disorders including malformations and disruptions. Starting from 19 to 20 weeks of gestation, prenatal magnetic resonance imaging (MRI) can reliably study the developing cerebellum. Pre- and postnatal neuroimaging plays a key role in the diagnostic work-up of congenital cerebellar abnormalities. Diagnostic criteria for cerebellar malformations and disruptions are based mostly on neuroimaging findings. The diagnosis of a Dandy-Walker malformation is based on the presence of hypoplasia, elevation, and counterclockwise upward rotation of the cerebellar vermis and cystic dilatation of the fourth ventricle, which extends posteriorly filling out the posterior fossa. For the diagnosis of Joubert syndrome, the presence of the molar tooth sign (thickened, elongated, and horizontally orientated superior cerebellar peduncles and an abnormally deep interpeduncular fossa) is needed. The diagnostic criteria of rhombencephalosynapsis include a complete or partial absence of the cerebellar vermis and continuity of the cerebellar hemispheres across the midline. Unilateral cerebellar hypoplasia is defined by the complete aplasia or hypoplasia of one cerebellar hemisphere. Familiarity with these diagnostic criteria as well as the broad spectrum of additional neuroimaging findings is important for a correct pre- and postnatal diagnosis. A correct diagnosis is essential for management, prognosis, and counseling of the affected children and their family. KEYWORDS: Cerebellum; Fetal; Malformations; Neuroimaging
PMID 26166429 DOI: 10.1007/s12311-015-0699-z
Calm1 signaling pathway is essential for the migration of mouse precerebellar neurons.
Development. 2015 Jan 15;142(2):375-84. doi: 10.1242/dev.112680. Epub 2014 Dec 17.
Kobayashi H1, Saragai S2, Naito A2, Ichio K2, Kawauchi D2, Murakami F2.
The calcium ion regulates many aspects of neuronal migration, which is an indispensable process in the development of the nervous system. Calmodulin (CaM) is a multifunctional calcium ion sensor that transduces much of the signal. To better understand the role of Ca(2+)-CaM in neuronal migration, we investigated mouse precerebellar neurons (PCNs), which undergo stereotyped, long-distance migration to reach their final position in the developing hindbrain. In mammals, CaM is encoded by three non-allelic CaM (Calm) genes (Calm1, Calm2 and Calm3), which produce an identical protein with no amino acid substitutions. We found that these CaM genes are expressed in migrating PCNs. When the expression of CaM from this multigene family was inhibited by RNAi-mediated acute knockdown, inhibition of Calm1 but not the other two genes caused defective PCN migration. Many PCNs treated with Calm1 shRNA failed to complete their circumferential tangential migration and thus failed to reach their prospective target position. Those that did reach the target position failed to invade the depth of the hindbrain through the required radial migration. Overall, our results suggest the participation of CaM in both the tangential and radial migration of PCNs. © 2015. Published by The Company of Biologists Ltd. KEYWORDS: Calcium signaling; Calm1; Migration; Pontine nuclei; Precerebellar neuron
Development of the cerebellum: simple steps to make a 'little brain'
Development. 2014 Nov;141(21):4031-41. doi: 10.1242/dev.106559.
Butts T1, Green MJ2, Wingate RJ3.
Abstract - Review
The cerebellum is a pre-eminent model for the study of neurogenesis and circuit assembly. Increasing interest in the cerebellum as a participant in higher cognitive processes and as a locus for a range of disorders and diseases make this simple yet elusive structure an important model in a number of fields. In recent years, our understanding of some of the more familiar aspects of cerebellar growth, such as its territorial allocation and the origin of its various cell types, has undergone major recalibration. Furthermore, owing to its stereotyped circuitry across a range of species, insights from a variety of species have contributed to an increasingly rich picture of how this system develops. Here, we review these recent advances and explore three distinct aspects of cerebellar development - allocation of the cerebellar anlage, the significance of transit amplification and the generation of neuronal diversity - each defined by distinct regulatory mechanisms and each with special significance for health and disease. © 2014. Published by The Company of Biologists Ltd. KEYWORDS: Atoh1; Autistic spectrum disorder; Granule cell; Medulloblastoma; Ptf1a; Purkinje cell
Abnormal cerebellar development and Purkinje cell defects in Lgl1-Pax2 conditional knockout mice
Dev Biol. 2014 Nov 1;395(1):167-81. doi: 10.1016/j.ydbio.2014.07.007. Epub 2014 Jul 19.
Hou C1, Ding L1, Zhang J1, Jin Y1, Sun C1, Li Z1, Sun X1, Zhang T1, Zhang A1, Li H2, Gao J3.
Lgl1 was initially identified as a tumour suppressor in flies and is characterised as a key regulator of epithelial polarity and asymmetric cell division. A previous study indicated that More-Cre-mediated Lgl1 knockout mice exhibited significant brain dysplasia and died within 24h after birth. To overcome early neonatal lethality, we generated Lgl1 conditional knockout mice mediated by Pax2-Cre, which is expressed in almost all cells in the cerebellum, and we examined the functions of Lgl1 in the cerebellum. Impaired motor coordination was detected in the mutant mice. Consistent with this abnormal behaviour, homozygous mice possessed a smaller cerebellum with fewer lobes, reduced granule precursor cell (GPC) proliferation, decreased Purkinje cell (PC) quantity and dendritic dysplasia. Loss of Lgl1 in the cerebellum led to hyperproliferation and impaired differentiation of neural progenitors in ventricular zone. Based on the TUNEL assay, we observed increased apoptosis in the cerebellum of mutant mice. We proposed that impaired differentiation and increased apoptosis may contribute to decreased PC quantity. To clarify the effect of Lgl1 on cerebellar granule cells, we used Math1-Cre to specifically delete Lgl1 in granule cells. Interestingly, the Lgl1-Math1 conditional knockout mice exhibited normal proliferation of GPCs and cerebellar development. Thus, we speculated that the reduction in the proliferation of GPCs in Lgl1-Pax2 conditional knockout mice may be secondary to the decreased number of PCs, which secrete the mitogenic factor Sonic hedgehog to regulate GPC proliferation. Taken together, these findings suggest that Lgl1 plays a key role in cerebellar development and folia formation by regulating the development of PCs. Copyright © 2014. Published by Elsevier Inc. KEYWORDS: Cerebellar development; Granule cell; Lgl1; Purkinje cells PMID 25050931
Ectopic cerebellar cell migration causes maldevelopment of Purkinje cells and abnormal motor behaviour in Cxcr4 null mice
PLoS One. 2014 Feb 7;9(2):e86471. doi: 10.1371/journal.pone.0086471. eCollection 2014. Huang GJ1, Edwards A2, Tsai CY3, Lee YS3, Peng L3, Era T4, Hirabayashi Y5, Tsai CY6, Nishikawa S7, Iwakura Y8, Chen SJ3, Flint J2. Author information
Abstract SDF-1/CXCR4 signalling plays an important role in neuronal cell migration and brain development. However, the impact of CXCR4 deficiency in the postnatal mouse brain is still poorly understood. Here, we demonstrate the importance of CXCR4 on cerebellar development and motor behaviour by conditional inactivation of Cxcr4 in the central nervous system. We found CXCR4 plays a key role in cerebellar development. Its loss leads to defects in Purkinje cell dentritogenesis and axonal projection in vivo but not in cell culture. Transcriptome analysis revealed the most significantly affected pathways in the Cxcr4 deficient developing cerebellum are involved in extra cellular matrix receptor interactions and focal adhesion. Consistent with functional impairment of the cerebellum, Cxcr4 knockout mice have poor coordination and balance performance in skilled motor tests. Together, these results suggest ectopic the migration of granule cells impairs development of Purkinje cells, causes gross cerebellar anatomical disruption and leads to behavioural motor defects in Cxcr4 null mice.
The normal cerebellum at birth has a sheath of immature neuroblasts, which are referred to as
Obersteiner’s layer (external granular layer)
- a sheath of immature neuroblasts present at birth
- located in the molecular layer superficial region
- migrating cells from this layer form the internal granular cell layer
- cell layer begins to diminish at 2 to 3 months after birth
- layer disappears by 12 months postnatally
The primary or undifferentiated stage (before 18 weeks of gestation): In this stage the internal granular layer was hardly distinguishable from layer of immature Purkinje cell. 2. The secondary or intermediate stage (from 18 weeks of gestation to 35 weeks of gestation): In this stage the internal granular layer was clearly visible and almost stable in thickness in all parts. 3. The tertiary or developing stage (35 to 40 weeks of gestation): In this stage the internal granular layer showed dramatic increase in thickness as the formation of cerebellar folia proceeds.
External granular cell layer bobbling: a distinct histomorphological feature of the developing human cerebellum
Clin Neuropathol. 2013 Jan-Feb;32(1):42-50. doi: 10.5414/NP300518.
Gelpi E1, Budka H, Preusser M. Author information
INTRODUCTION: The external granular layer (EGL) of the developing human cerebellum is detectable until an age of ~ 1 year. It has been described as a thin, evenly calibrated layer of germinal cells. We have repeatedly observed a distinct discontinuous bobbled configuration of the EGL (external granular layer bobbling = EGLB) in human infantile autopsy brains. AIM, MATERIALS AND METHODS: We investigated 106 human fetal and infantile postmortem brains (range of gestational week at birth: 14 - term; range of postpartal age: 0 - 500 days) for presence of EGLB and correlated it with gestational/postpartal age, gender, developmental stage of cerebellar cortex, medical history and neuropathological findings. RESULTS: EGLB was detectable in 38/106 (35.8%) cases. EGLB presents as focal series of uniform knob-like protrusions of the EGL. In the notches between individual knobs, capillaries penetrate from the primitive leptomeningeal vascular plexus into the molecular layer. We found EGLB predominantly in depths of fissures of cerebellar hemispheres, vermis and/or tonsils. Presence of EGLB was statistically significantly more common in liveborn cases who died after gestational week 25 and cases with higher maturity grade of the cerebellar cortex, respectively. There was no gender difference. EGLB was not associated with medical history or neuropathological findings. CONCLUSIONS: EGLB is a distinct histomorphological feature of the developing cerebellum, which is predominantly found in infants. Our data indicate that EGLB is a physiological phenomenon occuring during cerebellar development at a certain gestational age, although we cannot exclude that it represents an artifact related to tissue fixation. In any case, recognition of this recurring feature is relevant for the practicing neuropathologist and should not be interpreted as a cerebellar migration disorder.
Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient
Orphanet J Rare Dis. 2012 Mar 27;7:18.
Burglen L, Chantot-Bastaraud S, Garel C, Milh M, Touraine R, Zanni G, Petit F, Afenjar A, Goizet C, Barresi S, Coussement A, Ioos C, Lazaro L, Joriot S, Desguerre I, Lacombe D, des Portes V, Bertini E, Siffroi JP, de Villemeur TB, Rodriguez D. Source Centre de Référence Maladies Rares « malformations et maladies congénitales du cervelet », Hôpital Trousseau-Paris, CHU de Lyon, CHU de Lille, Paris, France. email@example.com
BACKGROUND: Pontocerebellar hypoplasia (PCH) is a heterogeneous group of diseases characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. According to clinical features, seven subtypes of PCH have been described, PCH type 2 related to TSEN54 mutations being the most frequent. PCH is most often autosomal recessive though de novo anomalies in the X-linked gene CASK have recently been identified in patients, mostly females, presenting with intellectual disability, microcephaly and PCH (MICPCH). METHODS: Fourteen patients (12 females and two males; aged 16 months-14 years) presenting with PCH at neuroimaging and with clinical characteristics unsuggestive of PCH1 or PCH2 were included. The CASK gene screening was performed using Array-CGH and sequencing. Clinical and neuroradiological features were collected. RESULTS: We observed a high frequency of patients with a CASK mutation (13/14). Ten patients (8 girls and 2 boys) had intragenic mutations and three female patients had a Xp11.4 submicroscopic deletion including the CASK gene. All were de novo mutations. Phenotype was variable in severity but highly similar among the 11 girls and was characterized by psychomotor retardation, severe intellectual disability, progressive microcephaly, dystonia, mild dysmorphism, and scoliosis. Other signs were frequently associated, such as growth retardation, ophthalmologic anomalies (glaucoma, megalocornea and optic atrophy), deafness and epilepsy. As expected in an X-linked disease manifesting mainly in females, the boy hemizygous for a splice mutation had a very severe phenotype with nearly no development and refractory epilepsy. We described a mild phenotype in a boy with a mosaic truncating mutation. We found some degree of correlation between severity of the vermis hypoplasia and clinical phenotype. CONCLUSION: This study describes a new series of PCH female patients with CASK inactivating mutations and confirms that these patients have a recognizable although variable phenotype consisting of a specific form of pontocerebellar hypoplasia. In addition, we report the second male patient to present with a severe MICPCH phenotype and a de novo CASK mutation and describe for the first time a mildly affected male patient harboring a mosaic mutation. In our reference centre, CASK related PCH is the second most frequent cause of PCH. The identification of a de novo mutation in these patients enables accurate and reassuring genetic counselling.
A note on the definition and the development of cerebellar Purkinje cell zones
Cerebellum. 2012 Jun;11(2):422-5.
Voogd J. Source Dept. of Neuroscience, Erasmus Medical Center, Rotterdam, The Netherlands. firstname.lastname@example.org Abstract
The definition of Purkinje cell zones by their white matter compartments, their physiological properties, and their molecular identity and the birthdate of their Purkinje cells will be reviewed.
Early fetal development of the human cerebellum
Surg Radiol Anat. 2011 Aug;33(6):523-30. doi: 10.1007/s00276-011-0796-8. Epub 2011 Mar 6.
Cho KH1, Rodríguez-Vázquez JF, Kim JH, Abe H, Murakami G, Cho BH. Author information
Abstract Early cerebellum development in humans is poorly understood. The present study histologically examined sections from 20 human embryos and fetuses at 6 weeks (12-16 mm crown-rump length (CRL); 4 specimens), 7-9 weeks (21-39 mm CRL; 8 specimens), 11-12 weeks (70-90 mm CRL; 4 specimens) and 15-16 weeks (110-130 mm CRL; 4 specimens). During 7-9 weeks (approximate CRL 28 mm), the rhombic lip (a pair of thickenings of the alar plate) protruded dorsally, bent laterally, extended ventrolaterally and fused with the medially located midbrain. During that process, the primitive choroid plexus appeared to become involved in the cerebellar hemisphere to form a centrally located eosinophilic matrix. At that stage, the inferior olive had already developed in the thick medulla. Thus, the term 'bulbo-pontine extension' may represent an erroneous labeling of a caudal part of the rhombic lip. The cerebellar vermis developed much later than the hemisphere possibly from a midline dark cell cluster near the aqueduct. In the midline area after 12 weeks (80 mm CRL), the growing bilateral hemispheres seem to provide mechanical stress such as rotation and shear that cause the development of several fissures much deeper than those on the hemisphere. The rapidly growing surface germinal layer may be a minor contributor to this vermian fissure formation. The vermian fissures seem to enable inside involvement of the surface germinal cells, and to induce cytodifferentiation of the vermis. Consequently, in the early stages, it appears that the cerebellar hemisphere and vermis develop independently of each other.
Classification, diagnosis and potential mechanisms in pontocerebellar hypoplasia
Orphanet J Rare Dis. 2011 Jul 12;6:50.
Namavar Y, Barth PG, Poll-The BT, Baas F. Source Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Pontocerebellar Hypoplasia (PCH) is group of very rare, inherited progressive neurodegenerative disorders with prenatal onset. Up to now seven different subtypes have been reported (PCH1-7). The incidence of each subtype is unknown. All subtypes share common characteristics, including hypoplasia/atrophy of cerebellum and pons, progressive microcephaly, and variable cerebral involvement. Patients have severe cognitive and motor handicaps and seizures are often reported. Treatment is only symptomatic and prognosis is poor, as most patients die during infancy or childhood. The genetic basis of different subtypes has been elucidated, which makes prenatal testing possible in families with mutations. Mutations in three tRNA splicing endonuclease subunit genes were found to be responsible for PCH2, PCH4 and PCH5. Mutations in the nuclear encoded mitochondrial arginyl- tRNA synthetase gene underlie PCH6. The tRNA splicing endonuclease, the mitochondrial arginyl- tRNA synthetase and the vaccinia related kinase1 are mutated in the minority of PCH1 cases. These genes are involved in essential processes in protein synthesis in general and tRNA processing in particular. In this review we describe the neuroradiological, neuropathological, clinical and genetic features of the different PCH subtypes and we report on in vitro and in vivo studies on the tRNA splicing endonuclease and mitochondrial arginyl-tRNA synthetase and discuss their relation to pontocerebellar hypoplasia.
Cerebellum development and medulloblastoma
Curr Top Dev Biol. 2011;94:235-82.
Roussel MF, Hatten ME. Source Department of Tumor Cell Biology and Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
In the last 20 years, it has become clear that developmental genes and their regulators, noncoding RNAs including microRNAs and long-noncoding RNAs, within signaling pathways play a critical role in the pathogenesis of cancer. Many of these pathways were first identified in genetic screens in Drosophila and other lower organisms. Mammalian orthologs were subsequently identified and genes within the pathways cloned and found to regulate cell growth. Genes and pathways expressed during embryonic development, including the Notch, Wnt/β-Catenin, TGF-β/BMP, Shh/Patched, and Hippo pathways are mutated, lost, or aberrantly regulated in a wide variety of human cancers, including skin, breast, blood, and brain cancers, including medulloblastoma. These biochemical pathways affect cell fate determination, axis formation, and patterning during development and regulate tissue homeostasis and regeneration in adults. Medulloblastoma, the most common malignant nervous system tumor in childhood, are thought to arise from disruptions in cerebellar development [reviewed by Marino, S. (2005)]. Defining the extracellular cues and intracellular signaling pathways that control cerebellar neurogenesis, especially granule cell progenitor (GCP) proliferation and differentiation has been useful for developing models to unravel the mechanisms underlying medulloblastoma formation and growth. In this chapter, we will review the development of the cerebellar cortex, highlighting signaling pathways of potential relevance to tumorigenesis. Copyright © 2011 Elsevier Inc. All rights reserved.
Preterm delivery disrupts the developmental program of the cerebellum
PLoS One. 2011;6(8):e23449. Epub 2011 Aug 17.
Haldipur P, Bharti U, Alberti C, Sarkar C, Gulati G, Iyengar S, Gressens P, Mani S. Source National Brain Research Centre, Manesar, Haryana, India.
A rapid growth in human cerebellar development occurs in the third trimester, which is impeded by preterm delivery. The goal of this study was to characterize the impact of preterm delivery on the developmental program of the human cerebellum. Still born infants, which meant that all development up to that age had taken place in-utero, were age paired with preterm delivery infants, who had survived in an ex-utero environment, which meant that their development had also taken place outside the uterus. The two groups were assessed on quantitative measures that included molecular markers of granule neuron, purkinje neuron and bergmann glia differentiation, as well as the expression of the sonic hedgehog signaling pathway, that is important for cerebellar growth. We report that premature birth and development in an ex-utero environment leads to a significant decrease in the thickness and an increase in the packing density of the cells within the external granular layer and the inner granular layer well, as a reduction in the density of bergmann glial fibres. In addition, this also leads to a reduced expression of sonic hedgehog in the purkinje layer. We conclude that the developmental program of the cerebellum is specifically modified by events that follow preterm delivery.
Alcohol exposure decreases CREB binding protein expression and histone acetylation in the developing cerebellum
PLoS One. 2011;6(5):e19351. Epub 2011 May 31.
Guo W, Crossey EL, Zhang L, Zucca S, George OL, Valenzuela CF, Zhao X. Source Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States of America.
BACKGROUND: Fetal alcohol exposure affects 1 in 100 children making it the leading cause of mental retardation in the US. It has long been known that alcohol affects cerebellum development and function. However, the underlying molecular mechanism is unclear.
METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate that CREB binding protein (CBP) is widely expressed in granule and Purkinje neurons of the developing cerebellar cortex of naïve rats. We also show that exposure to ethanol during the 3(rd) trimester-equivalent of human pregnancy reduces CBP levels. CBP is a histone acetyltransferase, a component of the epigenetic mechanism controlling neuronal gene expression. We further demonstrate that the acetylation of both histone H3 and H4 is reduced in the cerebellum of ethanol-treated rats.
CONCLUSIONS/SIGNIFICANCE: These findings indicate that ethanol exposure decreases the expression and function of CBP in the developing cerebellum. This effect of ethanol may be responsible for the motor coordination deficits that characterize fetal alcohol spectrum disorders.
The p53 inhibitor MDM2 facilitates Sonic Hedgehog-mediated tumorigenesis and influences cerebellar foliation
PLoS One. 2011 Mar 18;6(3):e17884.
Malek R, Matta J, Taylor N, Perry ME, Mendrysa SM. Source Department of Basic Medical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, Indiana, United States of America.
Disruption of cerebellar granular neuronal precursor (GNP) maturation can result in defects in motor coordination and learning, or in medulloblastoma, the most common childhood brain tumor. The Sonic Hedgehog (Shh) pathway is important for GNP proliferation; however, the factors regulating the extent and timing of GNP proliferation, as well as GNP differentiation and migration are poorly understood. The p53 tumor suppressor has been shown to negatively regulate the activity of the Shh effector, Gli1, in neural stem cells; however, the contribution of p53 to the regulation of Shh signaling in GNPs during cerebellar development has not been determined. Here, we exploited a hypomorphic allele of Mdm2 (Mdm2(puro)), which encodes a critical negative regulator of p53, to alter the level of wild-type MDM2 and p53 in vivo. We report that mice with reduced levels of MDM2 and increased levels of p53 have small cerebella with shortened folia, reminiscent of deficient Shh signaling. Indeed, Shh signaling in Mdm2-deficient GNPs is attenuated, concomitant with decreased expression of the Shh transducers, Gli1 and Gli2. We also find that Shh stimulation of GNPs promotes MDM2 accumulation and enhances phosphorylation at serine 166, a modification known to increase MDM2-p53 binding. Significantly, loss of MDM2 in Ptch1(+/-) mice, a model for Shh-mediated human medulloblastoma, impedes cerebellar tumorigenesis. Together, these results place MDM2 at a major nexus between the p53 and Shh signaling pathways in GNPs, with key roles in cerebellar development, GNP survival, cerebellar foliation, and MB tumorigenesis.
Development of axon-target specificity of ponto-cerebellar afferents
PLoS Biol. 2011 Feb 8;9(2):e1001013.
Kalinovsky A, Boukhtouche F, Blazeski R, Bornmann C, Suzuki N, Mason CA, Scheiffele P. Source Department of Physiology & Cellular Biophysics and Department of Neuroscience, Columbia University, New York, New York, United States of America.
The function of neuronal networks relies on selective assembly of synaptic connections during development. We examined how synaptic specificity emerges in the pontocerebellar projection. Analysis of axon-target interactions with correlated light-electron microscopy revealed that developing pontine mossy fibers elaborate extensive cell-cell contacts and synaptic connections with Purkinje cells, an inappropriate target. Subsequently, mossy fiber-Purkinje cell connections are eliminated resulting in granule cell-specific mossy fiber connectivity as observed in mature cerebellar circuits. Formation of mossy fiber-Purkinje cell contacts is negatively regulated by Purkinje cell-derived BMP4. BMP4 limits mossy fiber growth in vitro and Purkinje cell-specific ablation of BMP4 in mice results in exuberant mossy fiber-Purkinje cell interactions. These findings demonstrate that synaptic specificity in the pontocerebellar projection is achieved through a stepwise mechanism that entails transient innervation of Purkinje cells, followed by synapse elimination. Moreover, this work establishes BMP4 as a retrograde signal that regulates the axon-target interactions during development.
PMID 21346800 [PubMed - indexed for MEDLINE] PMCID PMC3035609
Bergmann glia and the recognition molecule CHL1 organize GABAergic axons and direct innervation of Purkinje cell dendrites
Ango F, Wu C, Van der Want JJ, Wu P, Schachner M, Huang ZJ. PLoS Biol. 2008 Apr 29;6(4):e103.
The geometric and subcellular organization of axon arbors distributes and regulates electrical signaling in neurons and networks, but the underlying mechanisms have remained elusive. In rodent cerebellar cortex, stellate interneurons elaborate characteristic axon arbors that selectively innervate Purkinje cell dendrites and likely regulate dendritic integration. We used GFP BAC transgenic reporter mice to examine the cellular processes and molecular mechanisms underlying the development of stellate cell axons and their innervation pattern. We show that stellate axons are organized and guided towards Purkinje cell dendrites by an intermediate scaffold of Bergmann glial (BG) fibers. The L1 family immunoglobulin protein Close Homologue of L1 (CHL1) is localized to apical BG fibers and stellate cells during the development of stellate axon arbors. In the absence of CHL1, stellate axons deviate from BG fibers and show aberrant branching and orientation. Furthermore, synapse formation between aberrant stellate axons and Purkinje dendrites is reduced and cannot be maintained, leading to progressive atrophy of axon terminals. These results establish BG fibers as a guiding scaffold and CHL1 a molecular signal in the organization of stellate axon arbors and in directing their dendritic innervation.
Development of human cerebellar granular layer: a morphometric study
No To Hattatsu. 1992 Jul;24(4):327-34.
[Article in Japanese] Yamaguchi K1, Goto N, Nara T. Author information
Abstract Development of the cerebellar granular layer, the external granular layer (EGL) and the internal granular layer (IGL), was studied morphologically to make complete serial sections of the brain from human fetuses ranging 12 to 40 weeks' gestation (WG). To examine the chronological changes and the regional differences, we measured the thickness of the layer microscopically among five different parts of the cerebellum: anterior lobe/hemisphere (AH), anterior lobe/vermis (AV), posterior lobe/hemisphere (PH), posterior lobe/vermis (PV) and flocculus (FL). EGL was the most superficial layer composed of densely packed undifferentiated cells. Its thickness showed little changes during the fetal period of 12-40 WG for all parts except FL where EGL was thicker than those in other parts and made a gradual attenuation with development. We noticed at least three stages in the fetal development of IGL: 1) the primary or undifferentiated stage (before 18 WG) when IGL was hardly distinguishable from the layer of immature Purkinje cells (PCL); 2) the secondary or intermediate stage (18 to 30 or 35 WG) when it was clearly visible and almost stable in thickness for all parts; 3) the tertiary or developing stage (30 or 35 to 40 WG) when it showed a dramatic increase in thickness as the formation of cerebellar folia was proceeding. During the intermediate stage the Lamina dissecans was observed between PCL and IGL typically in PH. Regional differences were detected in a period of transition from the intermediate to the developing stage among each part: the developing stage appeared earliest in AV and FL and latest in PH.(ABSTRACT TRUNCATED AT 250 WORDS)
- Obersteiner H; Der feinese Bau der Kleinhirnride bein Menschen und bei Tieren. (The fine structure of the cerebellar cortex in humans and in animals.) Biol Zentralb, 1883; 3:145-155.