Substitution of lost neurons by neurotransplantation would be a possible management of advanced degenerative cerebellar ataxias in which insufficient cerebellar reserve remains. In this study, we examined the volume and structure of solid embryonic cerebellar grafts in adult Lurcher mice, a model of olivocerebellar degeneration, and their healthy littermates. Grafts taken from enhanced green fluorescent protein (EGFP)-positive embryos were injected into the cerebellum of host mice. Two or six months later, the brains were examined histologically. The grafts were identified according to the EGFP fluorescence in frozen sections and their volumes were estimated using the Cavalieri principle. For gross histological evaluation, graft-containing slices were processed using Nissl and hematoxylin-eosin staining. Adjustment of the volume estimation approach suggested that it is reasonable to use all sections without sampling, but that calculation of values for up to 20% of lost section using linear interpolation does not constitute substantial error. Mean graft volume was smaller in Lurchers than in healthy mice when examined 6 months after the transplantation. We observed almost no signs of graft destruction. In some cases, compact grafts disorganized the structure of the host's cerebellar cortex. In Lurchers, the grafts had a limited contact with the host's cerebellum. Also, graft size was of greater variability in Lurchers than in healthy mice. The results are in compliance with our previous findings that Lurcher phenotype-associated factors have a negative effect on graft development. These factors can hypothetically include cerebellar morphology, local tissue milieu, or systemic factors such as immune system abnormalities.

• Keywords
• Cerebellum, Lurcher mice, Neurotransplantation, Olivocerebellar degeneration,
• MeSH
• Cerebellar Ataxia pathology   MeSH
• Disease Models, Animal * MeSH
• Cerebellum * pathology   MeSH
• Mice, Transgenic * MeSH
• Mice MeSH
• Brain Tissue Transplantation methods   MeSH
• Green Fluorescent Proteins genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• enhanced green fluorescent protein MeSH Browser
• Green Fluorescent Proteins MeSH

Spinocerebellar ataxias (SCAs) represent a large group of hereditary degenerative diseases of the nervous system, in particular the cerebellum, and other systems that manifest with a variety of progressive motor, cognitive, and behavioral deficits with the leading symptom of cerebellar ataxia. SCAs often lead to severe impairments of the patient's functioning, quality of life, and life expectancy. For SCAs, there are no proven effective pharmacotherapies that improve the symptoms or substantially delay disease progress, i.e., disease-modifying therapies. To study SCA pathogenesis and potential therapies, animal models have been widely used and are an essential part of pre-clinical research. They mainly include mice, but also other vertebrates and invertebrates. Each animal model has its strengths and weaknesses arising from model animal species, type of genetic manipulation, and similarity to human diseases. The types of murine and non-murine models of SCAs, their contribution to the investigation of SCA pathogenesis, pathological phenotype, and therapeutic approaches including their advantages and disadvantages are reviewed in this paper. There is a consensus among the panel of experts that (1) animal models represent valuable tools to improve our understanding of SCAs and discover and assess novel therapies for this group of neurological disorders characterized by diverse mechanisms and differential degenerative progressions, (2) thorough phenotypic assessment of individual animal models is required for studies addressing therapeutic approaches, (3) comparative studies are needed to bring pre-clinical research closer to clinical trials, and (4) mouse models complement cellular and invertebrate models which remain limited in terms of clinical translation for complex neurological disorders such as SCAs.

• Keywords
• Genetics, Models, Murine, Non-murine, Pathogenesis, Spinocerebellar ataxias, Therapies, Translational,
• MeSH
• Consensus MeSH
• Quality of Life * MeSH
• Models, Animal MeSH
• Cerebellum pathology   MeSH
• Mice MeSH
• Spinocerebellar Ataxias * diagnosis   genetics   therapy   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Neural stem cells are fundamental to development of the central nervous system (CNS)-as well as its plasticity and regeneration-and represent a potential tool for neuro transplantation therapy and research. This study is focused on examination of the proliferation dynamic and fate of embryonic neural stem cells (eNSCs) under differentiating conditions. In this work, we analyzed eNSCs differentiating alone and in the presence of sonic hedgehog (SHH) or triiodothyronine (T3) which play an important role in the development of the CNS. We found that inhibition of the SHH pathway and activation of the T3 pathway increased cellular health and survival of differentiating eNSCs. In addition, T3 was able to increase the expression of the gene for the receptor smoothened (Smo), which is part of the SHH signaling cascade, while SHH increased the expression of the T3 receptor beta gene (Thrb). This might be the reason why the combination of SHH and T3 increased the expression of the thyroxine 5-deiodinase type III gene (Dio3), which inhibits T3 activity, which in turn affects cellular health and proliferation activity of eNSCs.

• Keywords
• cell differentiation, embryonic neural stem cells, sonic hedgehog, triiodothyronine,
• MeSH
• Iodide Peroxidase genetics   metabolism   MeSH
• Cells, Cultured MeSH
• Mouse Embryonic Stem Cells cytology   metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Neural Stem Cells cytology   metabolism   MeSH
• Neurogenesis * MeSH
• Hedgehog Proteins genetics   metabolism   MeSH
• Smoothened Receptor genetics   metabolism   MeSH
• Triiodothyronine metabolism   MeSH
• Thyroid Hormone Receptors beta genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• iodothyronine deiodinase type III MeSH Browser
• Iodide Peroxidase MeSH
• Hedgehog Proteins MeSH
• Smoothened Receptor MeSH
• Shh protein, mouse MeSH Browser
• Smo protein, mouse MeSH Browser
• Triiodothyronine MeSH
• Thyroid Hormone Receptors beta MeSH

Cerebellar diseases causing substantial cell loss often lead to severe functional deficits and restoration of cerebellar function is difficult. Neurotransplantation therapy could become a hopeful method, but there are still many limitations and unknown aspects. Studies in a variety of cerebellar mutant mice reflecting heterogeneity of human cerebellar degenerations show promising results as well as new problems and questions to be answered. The aim of this work was to compare the development of embryonic cerebellar grafts in adult B6CBA Lurcher and B6.BR pcd mutant mice and strain-matched healthy wild type mice. Performance in the rotarod test, graft survival, structure, and volume was examined 2 months after the transplantation or sham-operation. The grafts survived in most of the mice of all types. In both B6CBA and B6.BR wild type mice and in pcd mice, colonization of the host's cerebellum was a common finding, while in Lurcher mice, the grafts showed a low tendency to infiltrate the host's cerebellar tissue. There were no significant differences in graft volume between mutant and wild type mice. Nevertheless, B6CBA mice had smaller grafts than their B6.BR counterparts. The transplantation did not improve the performance in the rotarod test. The study showed marked differences in graft integration into the host's cerebellum in two types of cerebellar mutants, suggesting disease-specific factors influencing graft fate.

• Keywords
• Ataxia, Cerebellar degeneration, Lurcher mouse, Neurotransplantation, Pcd mouse,
• MeSH
• Disease Models, Animal * MeSH
• Cerebellum physiology   transplantation   MeSH
• Mice, Neurologic Mutants MeSH
• Mice, Inbred C57BL MeSH
• Mice, Inbred CBA MeSH
• Mice MeSH
• Cerebellar Diseases pathology   therapy   MeSH
• Neurodegenerative Diseases pathology   therapy   MeSH
• Graft Survival physiology   MeSH
• Fetal Tissue Transplantation methods   MeSH
• Brain Tissue Transplantation methods   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH