Pattern formation during development of the embryonic cerebellum

Dastjerdi, F. V.; Consalez, G. Giacomo; Hawkes, Richard

doi:10.3389/fnana.2012.00010

Cited by 42 publications

(41 citation statements)

References 154 publications

(231 reference statements)

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“…In line with this, approximately 30.7±2.6% (19–48%) of PCs were transfected by IUE without affecting other cerebellar cell types (Figure. 3E, Figure S4B–E in Supplement 1) (27, 44). Using this in vivo manipulation, we reduced Foxp2 expression approximately 40.1±2.8% in vivo in the mouse cerebellum at P7 (Figure 3D).…”

Section: Resultsmentioning

confidence: 99%

“…We demonstrate that sumoylation of FOXP2 plays a critical role in transcription regulation, neuronal development, motor functions and USVs, specifically in the cerebellum. The timing of FOXP2 sumoylation in the cerebellum occurs during a critical period in the formation of the cerebellar neuronal network when dendritic arborization, synaptogenesis, and clustering of potassium channels take place (44, 54). This network is essential for normal cerebellar functions that are at risk in neurodevelopmental disorders such as ASD (15, 16, 18, 19).…”

Section: Discussionmentioning

confidence: 99%

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Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development

Usui

Harper

et al. 2017

Biological Psychiatry

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Background Mutations in the gene encoding the transcription factor forkhead box P2, FOXP2, result in brain developmental abnormalities including reduced gray matter in both human patients and rodent models, and speech and language deficits. However, neither the region-specific function of FOXP2 in the brain, in particular the cerebellum, nor the effects of any post-translational modifications of FOXP2 in the brain and disorders have been explored. Methods We characterized sumoylation of FOXP2 biochemically, and analyzed the region-specific function and sumoylation of FOXP2 in the developing mouse cerebellum. Using in utero electroporation to manipulate the sumoylation-state of Foxp2 as well as Foxp2 expression levels in Purkinje cells (PCs) of the cerebellum in vivo, we reduced Foxp2 expression approximately 40% in the mouse cerebellum. Such a reduction approximates the haploinsufficiency observed in human patients who demonstrate speech and language impairments. Results We identified sumoylation of FOXP2 at K674 (K673 in mouse) in the cerebellum of neonates. In vitro co-immunoprecipitation and in vivo colocalization experiments suggest that PIAS3 acts as the SUMO E3 ligase for FOXP2 sumoylation. This sumoylation modifies transcriptional regulation by FOXP2. We demonstrate that Foxp2 sumoylation is required for regulation of cerebellar motor function and vocal communication, likely through dendritic outgrowth and arborization of PCs in the mouse cerebellum. Conclusions Sumoylation of Foxp2 in neonatal mouse cerebellum regulates PC development as well as motor functions and vocal communication, demonstrating evidence for sumoylation in regulating mammalian behaviors.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development

Usui

Harper

et al. 2017

Biological Psychiatry

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“…Because we argue that much cerebellar patterning is built around a PC zone and stripe scaffold, we begin with a brief review of the origins of PC zones and stripes [reviewed in Herrup and Kuemerle (1997); Armstrong and Hawkes (2000); Larouche and Hawkes (2006); Sillitoe and Joyner (2007); Apps and Hawkes (2009); Dastjerdi et al (2012); Sillitoe and Hawkes (2013)]. The cerebellar primordium arises from the rostral metencephalon between E8.5 and E9.5 (e.g., Wang et al, 2005; Sillitoe and Joyner, 2007: all timings are for mice).…”

Section: Review Of Cerebellar Compartmentationmentioning

confidence: 99%

The compartmental restriction of cerebellar interneurons

Consalez¹,

Hawkes²

2013

Front. Neural Circuits

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The Purkinje cells (PC's) of the cerebellar cortex are subdivided into multiple different molecular phenotypes that form an elaborate array of parasagittal stripes. This array serves as a scaffold around which afferent topography is organized. The ways in which cerebellar interneurons may be restricted by this scaffolding are less well-understood. This review begins with a brief survey of cerebellar topography. Next, it reviews the development of stripes in the cerebellum with a particular emphasis on the embryological origins of cerebellar interneurons. These data serve as a foundation to discuss the hypothesis that cerebellar compartment boundaries also restrict cerebellar interneurons, both excitatory [granule cells, unipolar brush cells (UBCs)] and inhibitory (e.g., Golgi cells, basket cells). Finally, it is proposed that the same PC scaffold that restricts afferent terminal fields to stripes may also act to organize cerebellar interneurons.

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“…In the cerebellum, Purkinje cells form clusters deep within the cerebellar hemispheres until Reelin, secreted by the migrating granule neurons in the external granular layer (D'Arcangelo et al 1995(D'Arcangelo et al , 1997, binds to Apoer2 or Vldlr receptors on the Purkinje cells and activates a protein kinase cascade that (ultimately) decreases inter-Purkinje adhesion and allows dispersion of the embryonic clusters. Thus, liberated, the Purkinje cells form their characteristic stripes and begin to establish connections within and outside of the cerebellum (Dastjerdi et al 2012). Infants with mutations of the Reelin pathway are severely developmentally impaired with marked hypotonia at birth, marked global delays in development, and onset of generalized epilepsy at an early age (Hourihane et al 1993).…”

Section: Variant Lissencephaliesmentioning

confidence: 99%

Malformations of Cortical Development and Epilepsy

Barkovich

Dobyns²,

Guerrini

2015

Cold Spring Harbor Perspectives in Medicine

120

108

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Malformations of cortical development (MCDs) are an important cause of epilepsy and an extremely interesting group of disorders from the perspective of brain development and its perturbations. Many new MCDs have been described in recent years as a result of improvements in imaging, genetic testing, and understanding of the effects of mutations on the ability of their protein products to correctly function within the molecular pathways by which the brain functions. In this review, most of the major MCDs are reviewed from a clinical, embryological, and genetic perspective. The most recent literature regarding clinical diagnosis, mechanisms of development, and future paths of research are discussed.

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Pattern formation during development of the embryonic cerebellum

Cited by 42 publications

References 154 publications

Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development

Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development

The compartmental restriction of cerebellar interneurons

Malformations of Cortical Development and Epilepsy

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