Development of the cerebellum: simple steps to make a ‘little brain’

Butts, Thomas; Green, Mary J.; Wingate, Richard

doi:10.1242/dev.106559

Cited by 206 publications

(239 citation statements)

References 163 publications

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“…Post-mitotic GCs then migrate inward to form the IGL (Wingate 2001). PCs regulate the proliferative expansion of GC precursors in the EGL by the production of SHH (Goldowitz & Hamre 1998, Lewis et al 2004), a downstream target of RORα, and levels of SHH-dependent GC proliferation affect cerebellar size (Butts et al 2014). Our results indicate that TH-dependent processes in PCs affect non-autonomous aspects such as GC proliferation and differentiation.…”

Section: Mct8-deficient Pcs Disrupt Gc Precursor Proliferation and Pomentioning

confidence: 68%

MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development

Delbaere

Vancamp

Herck

et al. 2017

Journal of Endocrinology

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Inactivating mutations in the human SLC16A2 gene encoding the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) result in the Allan-Herndon-Dudley syndrome accompanied by severe locomotor deficits. The underlying mechanisms of the associated cerebellar maldevelopment were studied using the chicken as a model. Electroporation of an MCT8-RNAi vector into the cerebellar anlage of a 3-dayold embryo allowed knockdown of MCT8 in Purkinje cell precursors. This resulted in the downregulation of the thyroid hormone-responsive gene RORα and the Purkinje cell-specific differentiation marker LHX1/5 at day 6. MCT8 knockdown also results in a smaller and less complex dendritic tree at day 18 suggesting a pivotal role of MCT8 for cell-autonomous Purkinje cell maturation. Early administration of the thyroid hormone analogue 3,5,3′-triiodothyroacetic acid partially rescued early Purkinje cell differentiation. MCT8-deficient Purkinje cells also induced non-autonomous effects as they led to a reduced granule cell precursor proliferation, a thinner external germinal layer and a loss of PAX6 expression. By contrast, at day 18, the external germinal layer thickness was increased, with an increase in presence of Axonin-1-positive post-mitotic granule cells in the initial stage of radial migration. The concomitant accumulation of presumptive migrating granule cells in the molecular layer, suggests that inward radial migration to the internal granular layer is stalled. In conclusion, early MCT8 deficiency in Purkinje cells results in both cell-autonomous and non-autonomous effects on cerebellar development and indicates that MCT8 expression is essential from very early stages of development, providing a novel insight into the ontogenesis of the Allan-HerndonDudley syndrome.

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Section: Mct8-deficient Pcs Disrupt Gc Precursor Proliferation and Pomentioning

confidence: 68%

MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development

Delbaere

Vancamp

Herck

et al. 2017

Journal of Endocrinology

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“…The cerebellar cortex displays a highly stereotyped structure with three distinct layers: the molecular layer, the Purkinje cell layer and the granule cell layer (Fig. 3A) (Butts et al, 2014;Martinez et al, 2013;Millen and Gleeson, 2008). The major cell types in the cerebellum originate from two spatially distinct populations of neural progenitors (Fig.…”

Section: The Cerebellummentioning

confidence: 99%

Is this a brain which I see before me? Modeling human neural development with pluripotent stem cells

Suzuki

Vanderhaeghen

2015

Development

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The human brain is arguably the most complex structure among living organisms. However, the specific mechanisms leading to this complexity remain incompletely understood, primarily because of the poor experimental accessibility of the human embryonic brain. Over recent years, technologies based on pluripotent stem cells (PSCs) have been developed to generate neural cells of various types. While the translational potential of PSC technologies for disease modeling and/or cell replacement therapies is usually put forward as a rationale for their utility, they are also opening novel windows for direct observation and experimentation of the basic mechanisms of human brain development. PSC-based studies have revealed that a number of cardinal features of neural ontogenesis are remarkably conserved in human models, which can be studied in a reductionist fashion. They have also revealed species-specific features, which constitute attractive lines of investigation to elucidate the mechanisms underlying the development of the human brain, and its link with evolution.

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“…However, there are some differences. The vermis (a medial expansion of the cerebellum) is only seen in mammalian species (Butts et al, 2014), and the migration of granule neurons exhibits different patterns in different species. In the human embryo, the external granule layer reaches its peak thickness by gestational week 25, and the process of migration continues well into the first postnatal year.…”

Section: Expanding the Use Of The Chicken Embryo Modelmentioning

confidence: 99%

Cracking the Egg: Potential of the Developing Chicken as a Model System for Nonclinical Safety Studies of Pharmaceuticals

Bjørnstad

Austdal

Roald

et al. 2015

J Pharmacol Exp Ther

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The advance of perinatal medicine has improved the survival of extremely premature babies, thereby creating a new and heterogeneous patient group with limited information on appropriate treatment regimens. The developing fetus and neonate have traditionally been ignored populations with regard to safety studies of drugs, making medication during pregnancy and in newborns a significant safety concern. Recent initiatives of the Food and Drug Administration and European Medicines Agency have been passed with the objective of expanding the safe pharmacological treatment options in these patients. There is a consensus that neonates should be included in clinical trials. Prior to these trials, drug leads are tested in toxicity and pharmacology studies, as governed by several guidelines summarized in the multidisciplinary International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use M3 (R2). Pharmacology studies must be performed in the major organ systems: cardiovascular, respiratory, and central nervous system. The chicken embryo and fetus have features that make the chicken a convenient animal model for nonclinical safety studies in which effects on all of these organ systems can be tested. The developing chicken is inexpensive, accessible, and nutritionally self-sufficient with a short incubation time and is ideal for drug-screening purposes. Other high-throughput models have been implemented. However, many of these have limitations, including difficulty in mimicking natural tissue architecture and function (human stem cells) and obvious differences from mammals regarding the respiratory organ system and certain aspects of central nervous system development (Caenorhabditis elegans, zebrafish).This minireview outlines the potential and limitations of the developing chicken as an additional model for the early exploratory phase of development of new pharmaceuticals.

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Development of the cerebellum: simple steps to make a ‘little brain’

Cited by 206 publications

References 163 publications

MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development

MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development

Is this a brain which I see before me? Modeling human neural development with pluripotent stem cells

Cracking the Egg: Potential of the Developing Chicken as a Model System for Nonclinical Safety Studies of Pharmaceuticals

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