Development Of Cerebellar Cortex Research Articles

The development of chicken cerebellar cortex and the determination of AgNOR activity of the Purkinje cell nuclei

In this study, the embryonic and post-hatching development of the chicken cerebellar cortex, and the number, size and area of the silver-staining nucleolus-organizer regions (AgNORs) were determined in cerebellar Purkinje cells in layer-hen (Babcock-B380) embryos and chickens. The mean transverse diameter of the Purkinje cells and their nuclei, and the mean area of the Purkinje cell nucleus and AgNOR area increased during the entire experimental period. The mean ratio of the AgNOR area to the Purkinje cell nucleus area reached its highest value at the 15th day of incubation. There was no difference between the mean AgNOR numbers per nucleus. These findings provide reference data for future studies in this and related research topics, for example for establishing AgNOR parameters and we also hope that our data will be supplemented with other techniques such as PCNA and TUNEL in the near future.

Pleiotrophin and the Expression of Its Receptors during Development of the Human Cerebellar Cortex.

During embryonic and fetal development, the cerebellum undergoes several histological changes that require a specific microenvironment. Pleiotrophin (PTN) has been related to cerebral and cerebellar cortex ontogenesis in different species. PTN signaling includes PTPRZ1, ALK, and NRP-1 receptors, which are implicated in cell differentiation, migration, and proliferation. However, its involvement in human cerebellar development has not been described so far. Therefore, we investigated whether PTN and its receptors were expressed in the human cerebellar cortex during fetal and early neonatal development. The expression profile of PTN and its receptors was analyzed using an immunohistochemical method. PTN, PTPRZ1, and NRP-1 were expressed from week 17 to the postnatal stage, with variable expression among granule cell precursors, glial cells, and Purkinje cells. ALK was only expressed during week 31. These results suggest that, in the fetal and neonatal human cerebellum, PTN is involved in cell communication through granule cell precursors, Bergmann glia, and Purkinje cells via PTPRZ1, NRP-1, and ALK signaling. This communication could be involved in cell proliferation and cellular migration. Overall, the present study represents the first characterization of PTN, PTPRZ1, ALK, and NRP-1 expression in human tissues, suggesting their involvement in cerebellar cortex development.

Thyroid hormones regulate reelin expression in neuropsychiatric disorders.

The incidence and prevalence of hypothyroidism in pregnancy have increased over the past two decades, leading to the occurrence of neuropsychiatric disorders. However, the underlying mechanisms of thyroid hormone (TH)-regulated gene expression and neuropsychiatric development during the postnatal period remain unknown. Recent achievements have shown that reelin, a large extracellular glycoprotein, plays a crucial role in neuronal migration and localization during the development of neocortex and cerebellar cortex, thereby participating in the development of neuropsychiatric diseases. Reelin-induced neuronal migration requires triiodothyronine (T3) from the deiodination of thyroxine (T4) by fetal brain deiodinases. Previous studies have reported decreased reelin levels and abnormal gene expression, which are the same as the pathological alternations in reelin-induced neuropsychiatric disorders including schizophrenia and autism. Low T3 in the fetal brain due to hypothyroxinemia during pregnancy may be detrimental to neuronal migration, leading to neuropsychiatric disorders. In this review, we focus on the reelin expression between hypothyroidism and neuropsychiatric disorders.

Maternal exposure to the environmental pollutant "BDE-47" impairs the postnatal development of rat cerebellar cortex by modulating neuronal proliferation, synaptogenesis, NGF and BDNF pathways.

This study was designed to investigate the perinatal effect of BDE-47 exposure on the postnatal development of the rat cerebellar cortex. This study was carried out on 20 pregnant rats and 36 of their offspring. The pregnant rats were divided equally into control and BDE-47 treated mother groups; supplemented orally with BDE-47 (0.2 mg/kg/day from day 8 of gestation until the day of weaning). The offspring of both mother groups were subdivided, according to their developmental age, into three subgroups; PND14, PND21and PND42. SerumT3, T4 and TSH were assessed for dams and their offspring. Testing the motor coordination of the offspring via the rotarod test was conducted. Sections of the cerebellar cortex from offspring subgroups were stained with hematoxylin and eosin alongside immunohistochemical reactions and optical density of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), proliferating cell nuclear antigen (PCNA) and synaptophysin (SYN). Also, the thickness of different layers of the cerebellar cortex was histomorphometrically measured. BDE-47 treated mothers and their offspring subgroups showed a significant decrease in the serum free T3, T4 and increased TSH. The BDE-47 offspring displayed incoordination of the motor activity together with disturbed cytoarchitecture of the cerebellar cortical layers, and impaired migration of its germinative neuronal zones, particularly on PND14 and PND21. Moreover, these offspring displayed a decrease of the immune-expression and optical density of NGF, BDNF in the cerebellar cortical layers with impaired proliferation, and synaptogenesis. Maternal exposure to BDE-47 during pregnancy and lactation effectuated a potential deleterious retarding effect on the postnatal development of the rat cerebellar cortex mostly via modulating neuronal proliferation, synaptogenesis, NGF and BDNF pathways secondary to its hypothyroid effect.

The Effect of Induction of Maternal Hypothyroidism on Postnatal Cerebellar Cortex Development in Albino Rat Offspring and the Role of Thyroxin Replacement Therapy Histological, Immunohistochemical and Genetic Study

Background: Maternal thyroid hormones are necessary for the growth of the central nervous system before birth and their shortage can delay cerebellum development.Aim: This study aimed to evaluate the effect of maternal hypothyroidism induction on the development of the cerebellar cortex postnatally in offspring and to compare thyroxin replacement to mothers and postnatally to offspring.Material and Methods: Rat offspring were divided into 3 groups; group I (control), group II (hypothyroid); 15 offspring whose mothers received carbimazole (20 mg/kg/day orally) from the 1st gestational day to the 21st day of lactation. Group III (thyroid hormone replacement) included subgroup IIIa (15 rats) their mothers received carbimazole as group II and Levothyroxine (20 μg/kg/day subcutaneously) from the 10th day of gestation to 21st day of lactation, and subgroup IIIb (15 rats), their mothers received carbimazole as group II and offspring received Levothyroxine (20μg/kg/day subcutaneously) from day 1 postnatally. At the end of 1st, 2nd, and 3rd postnatal weeks, serum Thyroid-stimulating hormone, Free triiodothyronine, and thyroxin were estimated. Cerebellar cortex sections were stained with hematoxylin and eosin, Neurofilament, Myelin basic protein, and Bcl2 immunohistochemical stains. The real-time polymerase chain reaction was done for the reelin gene.Results: Group II showed a significantly reduced Free triiodothyronine, thyroxin, and increased Thyroid-stimulating hormone. Vacuolation in the external granular layer and delayed its disappearance and degeneration of Purkinje cells that increased with age were observed. Reduced myelination, neurofilament content, and Reelin gene expression in the offspring were also detected. Replacement therapy (group III) especially to the mothers (subgroup IIIa) revealed amelioration of these changes.Conclusion: Maternal hypothyroidism impaired development of the offspring cerebellar cortex. However, thyroxin replacement for mothers was more effective than the treatment of offspring. Therefore, treatment of hypothyroid mothers during pregnancy is essential to ensure adequate cerebellar cortex development.

Loss of prostatic acid phosphatase and α-synuclein cause motor circuit degeneration without altering cerebellar patterning.

Prostatic acid phosphatase (PAP), which is secreted by prostate, increases in some diseases such as prostate cancer. PAP is also present in the central nervous system. In this study we reveal that α-synuclein (Snca) gene is co-deleted/mutated in PAP null mouse. It is indicated that mice deficient in transmembrane PAP display neurological alterations. By using immunohistochemistry, cerebellar cortical neurons and zone and stripes pattern were studied in Pap-/- ;Snca-/- mouse cerebellum. We show that the Pap-/- ;Snca-/- cerebellar cortex development appears to be normal. Compartmentation genes expression such as zebrin II, HSP25, and P75NTR show the zone and stripe phenotype characteristic of the normal cerebellum. These data indicate that although aggregation of PAP and SNCA causes severe neurodegenerative diseases, PAP -/- with absence of the Snca does not appear to interrupt the cerebellar architecture development and zone and stripe pattern formation. These findings question the physiological and pathological role of SNCA and PAP during cerebellar development or suggest existence of the possible compensatory mechanisms in the absence of these genes.

Lgl1 deficiency disrupts hippocampal development and impairs cognitive performance in mice.

Cellular polarity is crucial for brain development and morphogenesis. Lethal giant larvae 1 (Lgl1) plays a crucial role in the establishment of cell polarity from Drosophila to mammalian cells. Previous studies have found the importance of Lgl1 in the development of cerebellar, olfactory bulb, and cerebral cortex. However, the role of Lgl1 in hippocampal development during the embryonic stage and function in adult mice is still unknown. In our study, we created Lgl1-deficient hippocampus mice by using Emx1-Cre mice. Histological analysis showed that the Emx1-Lgl1-/- mice exhibited reduced size of the hippocampus with severe malformations of hippocampal cytoarchitecture. These defects mainly originated from the disrupted hippocampal neuroepithelium, including increased cell proliferation, abnormal interkinetic nuclear migration, reduced differentiation, increased apoptosis, gradual disruption of adherens junctions, and abnormal neuronal migration. The radial glial scaffold was disorganized in the Lgl1-deficient hippocampus. Thus, Lgl1 plays a distinct role in hippocampal neurogenesis. In addition, the Emx1-Lgl1-/- mice displayed impaired behavioral performance in the Morris water maze and fear conditioning test.

Prolidase enzyme is required for extracellular matrix integrity and impacts on postnatal cerebellar cortex development.

The extracellular matrix is essential for brain development, lamination, and synaptogenesis. In particular, the basement membrane below the pial meninx (pBM) is required for correct cortical development. The last step in the catabolism of the most abundant protein in pBM, collagen Type IV, requires prolidase, an exopeptidase cleaving the imidodipeptides containing pro or hyp at the C-terminal end. Mutations impairing prolidase activity lead in humans to the rare disease prolidase deficiency characterized by severe skin ulcers and mental impairment. Thus, the dark-like (dal) mouse, in which the prolidase is knocked-out, was used to investigate whether the deficiency of prolidase affects the neuronal maturation during development of a brain cortex area. Focusing on the cerebellar cortex, thinner collagen fibers and disorganized pBM were found. Aberrant cortical granule cell proliferation and migration occurred, associated to defects in brain lamination, and in particular in maturation of Purkinje neurons and formation of synaptic contacts. This study deeply elucidates a link between prolidase activity and neuronal maturation shedding new light on the molecular basis of functional aspects in the prolidase deficiency.

Aberrant Development and Synaptic Transmission of Cerebellar Cortex in a VPA Induced Mouse Autism Model.

Autistic spectral disorder (ASD) is a prevalent neurodevelopmental disease that affects multiple brain regions. Both clinical and animal studies have revealed the possible involvement of the cerebellum in ASD pathology. In this study, we generated a rodent ASD model through a single prenatal administration of valproic acid (VPA) into pregnant mice, followed by cerebellar morphological and functional studies of the offspring. Behavioral studies showed that VPA exposure led to retardation of critical motor reflexes in juveniles and impaired learning in a tone-conditioned complex motor task in adults. These behavioral phenotypes were associated with premature migration and excess apoptosis of the granular cell (GC) precursor in the cerebellar cortex during the early postnatal period, and the decreased cell density and impaired dendritic arborization of the Purkinje neurons. On acute cerebellar slices, suppressed synaptic transmission of the Purkinje cells were reported in the VPA-treated mice. In summary, converging evidence from anatomical, electrophysiological and behavioral abnormalities in the VPA-treated mice suggest cerebellar pathology in ASD and indicate the potential values of motor dysfunction in the early diagnosis of ASD.

Pengaruh pemberian insektisida Furadan 3G terhadap perkembangan tuba neuralis embrio ayam ras

Background: Furadan 3G insecticide is widely used in agriculture sector. Aim: To explore the teratogenic effect on development of the neural tube and cerebellum of the chick embryo. Method: Eighty fertilized eggs were involved in this experiment and incubated until hatching and forty further (the half) were injected with Furadan 3G 11 mg/kg on the first day of the experiment while the other half were referred as control group. The specimen were studied on the day of 5th, 7th, 21st, 2 weeks and 4 weeks of incubation after hatching by preparing a transversal section and staining with M.E. Conclusion: the Furadan 3G interfered the development of cerebellar cortex.

A Peptidomic Approach to Characterize Peptides Involved in Cerebellar Cortex Development Leads to the Identification of the Neurotrophic Effects of Nociceptin

The cerebellum is a brain structure involved in motor and cognitive functions. The development of the cerebellar cortex (the external part of the cerebellum) is under the control of numerous factors. Among these factors, neuropeptides including PACAP or somatostatin modulate the survival, migration and/or differentiation of cerebellar granule cells. Interestingly, such peptides contributing to cerebellar ontogenesis usually exhibit a specific transient expression profile with a low abundance at birth, a high expression level during the developmental processes, which take place within the first two postnatal weeks in rodents, and a gradual decline toward adulthood. Thus, to identify new peptides transiently expressed in the cerebellum during development, rat cerebella were sampled from birth to adulthood, and analyzed by a semi-quantitative peptidomic approach. A total of 33 peptides were found to be expressed in the cerebellum. Among these 33 peptides, 8 had a clear differential expression pattern during development, 4 of them i.e. cerebellin 2, nociceptin, somatostatin and VGF [353-372], exhibiting a high expression level during the first two postnatal weeks followed by a significative decrease at adulthood. A focus by a genomic approach on nociceptin, confirmed that its precursor mRNA is transiently expressed during the first week of life in granule neurons within the internal granule cell layer of the cerebellum, and showed that the nociceptin receptor is also actively expressed between P8 and P16 by the same neurons. Finally, functional studies revealed a new role for nociceptin, acting as a neurotrophic peptide able to promote the survival and differentiation of developing cerebellar granule neurons.

Effect of valproic acid administration during pregnancy on postnatal development of cerebellar cortex and the possible protective role of folic acid.

Valproic acid (VPA), one of the most important antiepileptic drugs, proved to be inevitable for epileptic pregnant women to limit the hazards of convulsions on the foetuses and mothers. Periconceptional folic acid supple-mentation was investigated to protect against several birth defects. However, its role against VPA cerebellar toxicity was not properly investigated. The present study was conducted to evaluate the protective effect of folic acid against VPA cerebellar neurotoxicity. Twenty-four pregnant female albino rats were divided into three groups; group I (control group, did not receive any drugs), group II (given VPA at a dose of 50 mg/kg body weight once daily) and group III (given the same dose of VPA and 400 μg/kg of body weight folic acid once daily). Ten male offspring from each group were sacrificed at two ages: at 2 and 12 weeks after birth. Samples of cerebellar cortex were taken and prepared for light, electron microscopic examination, glial fibrillary acidic protein (GFAP) immunohistochemical study and histomorphometric analysis. The present study confirmed the neurotoxic effect of prenatal VPA on the cerebellar cortex, especially on Purkinje cells. The cells appeared shrunken, reduced in density, disorganised and surrounded by empty haloes. Nuclear damage and axon degeneration in the form of vacuolation, loss of organelles and absence of neurofilaments with myelin sheath depletion were detected. Concomitant supply of folic acid was shown to retain the normal architecture of Purkinje cells with their axons and nuclei. In many animals receiving folic acid, the thickness of all layers of the cortex increased up to that of the control groups, after being markedly reduced in VPA-treated groups. GFAP immunoreaction was also improved against the strong positive gliosis detected in VPA-treated groups. The present study confirmed the protective role of folic acid against the cerebellar neurotoxic effects of VPA prenatal exposure. It is recommended that folic acid supplements should be given to every epileptic pregnant mother treated with VPA. (Folia Morphol 2018; 77, 2: 201-209).

Adult Attention Deficit Hyperactivity Disorder : A Case Report

Background: Oseltamivir phosphate (OP) is preferred treatment for influenza with activity against influenza A and B. It is commonly recommended for the treatment and chemoprophylaxis in pregnancy and lactation. Serious neuropsychiatric adverse reactions were observed in patient treated with OP. Objective: This study aims to evaluate the effects of OP on prenatal and post-natal development of the albino rat cerebellar cortex. Material and methods: This study was carried out on 40 pregnant albino rats and 120 of their offspring of both sex, 3 from each mother. The pregnant rats were divided equally into 2 main groups A and B. Group A (control): it was subdivided equally into 2 subgroups A1 and A2. Group B (OP treated): it was subdivided equally into 2 subgroups B1 and B2. In group A, each rat mother was given 0.9 ml distilled water twice daily by oral gavage for successive 5 days. In group B, each rat mother was given 0.9 ml distilled water containing 1.35 mg OP twice daily by oral gavage for successive 5 days. Dosing started from the 15th to 19 th of pregnancy in subgroups A1 and B1 while it started from the 1st to 5th day after delivery in subgroups A2 and B2. Cerebelli were collected, on the 1st day of birth in subgroups A1 and B1, on the 7 th day of birth in subgroups A2 and B2, and on the 14 th day of birth in subgroups A1, A2, B1 and B2. The cerebelli of all subgroups were subjected to light microscopic study and the cerebelli of 14 days old offspring were subjected also, to transmission electron microscopic and morphometric studies and statistical analysis. Results: OP induced delayed development and neurotoxic effects on the cerebellar cortex of albino rat offspring whose mother dosed OP during pregnancy or during lactation. Conclusion: Oseltamivir phosphate induced pre and post-natal delayed development and neurotoxic insults on the cerebellar cortex of albino rat.

Pathobiological expression of the brain-derived neurotrophic factor (BDNF) in cerebellar cortex of sudden fetal and infant death victims

Brain-derived neurotrophic factor (BDNF), a neurotrophin of the central nervous system, is able to regulate neuronal differentiation and modulate synaptic plasticity, being particularly involved in the development of the cerebellar cortical structure. The main aim of this study was to delineate, by immunohistochemistry, the BDNF expression in human cerebellar cortex of victims of fetal and infant death. The study was performed on a total of 45 cases, aged between 25 gestational weeks and 6 postnatal months, including 29 victims of sudden fetal and infant death and 16 age-matched subjects who died of known causes (Controls). We observed, in sudden death groups compared with Controls, a significantly higher incidence of defective BDNF expression in granule layers of the cerebellar cortex, which was particularly evident in the posterior lobule, a region that participates in respiratory control. These results were related to maternal smoking, allowing to speculate that nicotine, in addition to the well-known damages, can exert adverse effects during cerebellar cortex development, in particular in hindering the BDNF expression in the posterior lobule. This implies modifications of synaptic transmission in the respiratory circuits, with obvious deleterious consequences on survival.

Stereological study of the effects of maternal diabetes on cerebellar cortex development in rat

Diabetes during pregnancy is associated with the deficits in balance and motor coordination and altered social behaviors in offspring. In the present study, we have investigated the effect of maternal diabetes and insulin treatment on the cerebellar volume and morphogenesis of the cerebellar cortex of rat neonates during the first two postnatal weeks. Sprague Dawley female rats were maintained diabetic from a week before pregnancy through parturition. At the end of pregnancy, the male offspring euthanized on postnatal days (P) 0, 7, and 14. Cavalieri's principle and fractionator methods were used to estimate the cerebellar volume, the thickness and the number of cells in the different layers of the cerebellar cortex. In spite of P0, there was a significant reduction in the cerebellar volume and the thickness of the external granule, molecular, and internal granule layers between the diabetic and the control animals. In diabetic group, the granular and purkinje cell densities were increased at P0. Moreover, the number of granular and purkinje cells in the cerebellum of diabetic neonates was reduced in comparison with the control group at P7 and P14. There were no significant differences in either the volume and thickness or the number of cells in the different layers of the cerebellar cortex between the insulin-treated diabetic group and controls. Our data indicate that diabetes in pregnancy disrupts the morphogenesis of cerebellar cortex. This dysmorphogenesis may be part of the cascade of events through which diabetes during pregnancy affects motor coordination and social behaviors in offspring.

Cerebellar cortex development in the weaver condition presents regional and age-dependent abnormalities without differences in Purkinje cells neurogenesis.

Ataxias are neurological disorders associated with the degeneration of Purkinje cells (PCs). Homozygous weaver mice (wv/wv) have been proposed as a model for hereditary cerebellar ataxia because they present motor abnormalities and PC loss. To ascertain the physiopathology of the weaver condition, the development of the cerebellar cortex lobes was examined at postnatal day (P): P8, P20 and P90. Three approaches were used: 1) quantitative determination of several cerebellar features; 2) qualitative evaluation of the developmental changes occurring in the cortical lobes; and 3) autoradiographic analyses of PC generation and placement. Our results revealed a reduction in the size of the wv/wv cerebellum as a whole, confirming previous results. However, as distinguished from these reports, we observed that quantified parameters contribute differently to the abnormal growth of the wv/wv cerebellar lobes. Qualitative analysis showed anomalies in wv/wv cerebellar cytoarchitecture, depending on the age and lobe analyzed. Such abnormalities included the presence of the external granular layer after P20 and, at P90, ectopic cells located in the molecular layer following several placement patterns. Finally, we obtained autoradiographic evidence that wild-type and wv/wv PCs presented similar neurogenetic timetables, as reported. However, the innovative character of this current work lies in the fact that the neurogenetic gradients of wv/wv PCs were not modified from P8 to P90. A tendency for the accumulation of late-formed PCs in the anterior and posterior lobes was found, whereas early-generated PCs were concentrated in the central and inferior lobes. These data suggested that wv/wv PCs may migrate properly to their final destinations. The extrapolation of our results to patients affected with cerebellar ataxias suggests that all cerebellar cortex lobes are affected with several age-dependent alterations in cytoarchitectonics. We also propose that PC loss may be regionally variable and not related to their neurogenetic timetables.

Neurotoxicological effects of nicotine on the embryonic development of cerebellar cortex of chick embryo during various stages of incubation.

Long-acting nicotine is known to exert pathological effects on almost all tissues including the cerebellar cortex. The present work was designed to elucidate the effect of nicotine on the development of cerebellar cortex of chick embryo during incubation period. The fertilized eggs of hen (Gallus gallus domesticus) were injected into the air space by a single dose of long acting nicotine (1.6 mg/kg/egg) at the 4th day of incubation. The embryos were taken out of the eggs on days 8, 12 and 16 of incubation. The cerebellum of the control and treated embryos at above ages were processed for histopathological examination. The TEM were examined at 16th day of incubation. The results of the present study revealed that, exposure to long-acting nicotine markedly influence the histogenesis of cerebellar cortex of chick embryo during the incubation period. At 8th day of incubation, nicotine delayed the differentiation of the cerebellar analge; especially the external granular layer (EGL) and inner cortical layer (ICL). Furthermore, at 12th day of incubation, the cerebellar foliation was irregular and the Purkinje cells not recognized. By 16th day of incubation, the cerebellar foliations were irregular with interrupted cerebellar cortex and irregular arrangement of Purkinje cells. Immunohistochemical analysis for antibody P53 protein revealed that the cerebellar cortex in all stages of nicotine treated groups possessed a moderate to weak reaction for P53 protein however; this reaction was markedly stronger in the cerebellar cortex of control groups. Moreover, the flow cytometric analysis confirmed that the percentage of apoptosis in control group was significantly higher compared with that of nicotine treated group. At the TEM level, the cerebellar Purkinje cells of 16th day of treated groups showed multiple subcellular alterations in compared with those of the corresponding control group. Such changes represented by appearing of vacuolated mitochondria, cisternal fragmentation of RER, irregular grooves of Golgi tubules. Also, multiple cytoplasmic vacuoles and aggregation of Nissl granules were recorded around pyknotic nucleus.

The Similar Expression Pattern of MHC Class I Molecules in Human and Mouse Cerebellar Cortex

The major histocompatibility complex (MHC) class I molecules are considered to be important in the immune system. However, the results reported in the past decade indicate that they also play important roles in the central nervous system. Here we examined the expression of MHC I and β2-microglobulin (β2m) in human and mouse cerebellar cortex. The results show that MHC I molecules are expressed both in human and mouse cerebellar cortex during brain development. The expression of H-2K(b)/D(b) is gradually increased with the development of mouse cerebellar cortex, but finally decreased to a very low level. Similarly, the expression of HLA-B/C genes is increased in developing human cerebellar cortex, but decreased after birth. The spatial and temporal expression of β2m overlaps mostly with that of HLA-B/C molecules, and they are co-expressed in Purkinje cells. Our findings provide a fundamental basis to reveal the functions of neuronal MHC class I molecules in the development of human cerebellum.

Effect of selenium in ameliorating the effect of induced perinatal hypothyroidism on postnatal rat cerebellar cortex development

Effect of selenium in ameliorating the effect of induced perinatal hypothyroidism on postnatal rat cerebellar cortex development

Constitutive activation of β-Catenin in neural progenitors results in disrupted proliferation and migration of neurons within the central nervous system

Wnt signaling is known to play crucial roles in the development of multiple organs as well as in cancer. In particular, constitutive activation of Wnt/β-Catenin signaling in distinct populations of forebrain or brainstem precursor cells has previously been shown to result in dramatic brain enlargement during embryonic stages of development as well as in the formation of medulloblastoma, a malignant brain tumor in childhood. In order to extend this knowledge to postnatal stages of both cerebral and cerebellar cortex development, we conditionally activated Wnt signaling by introducing a dominant active form of β-catenin in hGFAP-positive neural precursors. Such mutant mice survived up to 21 days postnatally. While the mice revealed enlarged ventricles and an initial expansion of the Pax6-positive ventricular zone, Pax6 expression and proliferative activity in the ventricular zone was virtually lost by embryonic day 16.5. Loss of Pax6 expression was not followed by expression of the subventricular zone marker Tbr2, indicating insufficient neuronal differentiation. In support of this finding, cortical thickness was severely diminished in all analyzed stages from embryonic day 14.5 to postnatal day 12, and appropriate layering was not detectable. Similarly, cerebella of hGFAP-cre::Ctnnb1(ex3)Fl/+ mice were hypoplastic and displayed severe lamination defects. Constitutively active β-Catenin induced inappropriate proliferation of granule neurons and inadequate development of Bergmann glia, thereby preventing regular migration of granule cells and normal cortical layering. We conclude that Wnt signaling has divergent roles in the central nervous system and that Wnt needs to be tightly controlled in a time- and cell type-specific manner.