Gli3 Controls Corpus Callosum Formation by Positioning Midline Guideposts During Telencephalic Patterning

Magnani, Dario; Hasenpusch‐Theil, Kerstin; Benadiba, Carine; Yu, Tian; Basson, M. Albert; Price, David J.; Lebrand, Cécile; Theil, Thomas

doi:10.1093/cercor/bhs303

Cited by 35 publications

(34 citation statements)

References 69 publications

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“…S4A-F′). Gli3 and Fgf8 are required for corticoseptal boundary patterning and callosal formation (Amaniti et al, 2013;Magnani et al, 2014;Moldrich et al, 2010). Their expression and that of Sprouty1, a target of Fgf signaling, appeared normal in Nf2 mutants (supplementary material Fig.…”

Section: Nf2 Is Required For Glial Wedge Developmentmentioning

confidence: 99%

“…Although it has long been recognized that the environment which callosal axons traverse is crucial for their pathfinding, how this environment is shaped is not well understood. Despite recent progress (Amaniti et al, 2013;Benadiba et al, 2012;Chinn et al, 2014;Magnani et al, 2014;Piper et al, 2009a;Shu et al, 2003a,b;Smith et al, 2006;Unni et al, 2012), our knowledge of what regulates the development of guideposts and expression of guidance molecules remains limited.…”

Section: Introductionmentioning

confidence: 99%

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The tumor suppressor Nf2 regulates corpus callosum development by inhibiting the transcriptional coactivator Yap

Lavado¹,

Ware²,

Paré³

et al. 2014

Journal of Cell Science

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The corpus callosum connects cerebral hemispheres and is the largest axon tract in the mammalian brain. Callosal malformations are among the most common congenital brain anomalies and are associated with a wide range of neuropsychological deficits. Crossing of the midline by callosal axons relies on a proper midline environment that harbors guidepost cells emitting guidance cues to instruct callosal axon navigation. Little is known about what controls the formation of the midline environment. We find that two components of the Hippo pathway, the tumor suppressor Nf2 (Merlin) and the transcriptional coactivator Yap (Yap1), regulate guidepost development and expression of the guidance cue Slit2 in mouse. During normal brain development, Nf2 suppresses Yap activity in neural progenitor cells to promote guidepost cell differentiation and prevent ectopic Slit2 expression. Loss of Nf2 causes malformation of midline guideposts and Slit2 upregulation, resulting in callosal agenesis. Slit2 heterozygosity and Yap deletion both restore callosal formation in Nf2 mutants. Furthermore, selectively elevating Yap activity in midline neural progenitors is sufficient to disrupt guidepost formation, upregulate Slit2 and prevent midline crossing. The Hippo pathway is known for its role in controlling organ growth and tumorigenesis. Our study identifies a novel role of this pathway in axon guidance. Moreover, by linking axon pathfinding and neural progenitor behaviors, our results provide an example of the intricate coordination between growth and wiring during brain development.

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Section: Nf2 Is Required For Glial Wedge Developmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The tumor suppressor Nf2 regulates corpus callosum development by inhibiting the transcriptional coactivator Yap

Lavado¹,

Ware²,

Paré³

et al. 2014

Journal of Cell Science

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show abstract

“…La ventralisation du télencéphale des mutants ciliaires ressemble à ce qui a été décrit chez les mutants Gli3 [22], anomalies qui avaient conduit à définir cet effecteur de la voie Hh comme un acteur majeur de la spécification du télencéphale dorsal [9]. Ainsi, il semblait raisonnable de postuler que les cils primaires étaient nécessaires à la spéci-fication du télencéphale dorsal via leur rôle dans la production de Gli3-R. Nous avons formellement validé cette hypothèse en réintroduisant la protéine Gli3-R chez les mutants ciliaires Rpgrip1l Ftm/Ftm en croisant ces souris avec la lignée Gli3 Δ699 qui exprime une forme tronquée de Gli3 fonctionnellement semblable à Gli3-R (knock-in Gli3 Δ699 au locus Gli3) [23].…”

Section: Cil Primaire Et Fermeture Du Tube Neuralunclassified

“…Ces cellules se différencient en position ectopique chez les mutants ciliaires, probablement suite au défaut de régionalisation précoce du télencéphale. Ce phénotype, semblable à celui qui est décrit chez les mutants Gli3 [22], peut être corrigé par la réintroduction de Gli3-R chez les doubles mutants Ftm -/-Gli3 Δ699 et Rfx3 -/-Gli3 Δ699 [45] (C. Laclef, manuscrit en préparation).…”

Section: Cil Primaire Et Transition Prolifération/différenciation Desunclassified

Le cil primaire, orchestrateur de la morphogenèse cérébrale

Laclef

2014

Med Sci (Paris)

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“…Nuclear factor I (Nfi), GLI-Kruppel family member GLI3 (Gli3) and Fibroblast growth factor receptor 1 (Fgfr1) signalling) to specify and migrate normally, and thus some knockout animals lacking these genes show defects in these populations and subsequently altered callosal development (Shu et al, 2003c;Steele-Perkins et al, 2005;Smith et al, 2006;Amaniti et al, 2013;Magnani et al, 2014).…”

Section: Midline Crossingmentioning

confidence: 99%

Contralateral targeting of the corpus callosum

Fenlon¹

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During development, the brain establishes billions of precise connections in order to perform its myriad functions. The largest of these connections in placental mammals is the corpus callosum, which is a large bundle of axons linking the two cortical hemispheres of the brain. Absence or gross malformation of this structure is a relatively common developmental disorder in humans, producing symptoms ranging from severe to mild cognitive, emotional and motor deficits. However, recent evidence suggests that the corpus callosum can also display subtle malformations that are not visible with traditional magnetic resonance imaging methods, and that these may be involved in neurodevelopmental disorders such as autism and schizophrenia. The possibility of callosal misconnectivity arising independently of the widely-studied process of midline crossing highlights the need to investigate other less well-understood stages of callosal development. One such process that may be disrupted after normal midline crossing of the corpus callosum is contralateral targeting, where axons must locate, innervate and stabilize in their appropriate contralateral cortical targets.This thesis focuses on understanding the normal process of contralateral targeting, as well as the nature of its dependence on neuronal activity and the molecular mechanisms that regulate it. To investigate these topics, diverse approaches including in utero electroporation, stereotaxic brain injection, sensory deprivation paradigms, tissuespecific RNA extraction and RNA sequencing were used in the mouse somatosensory cortex model system of callosal connectivity. Novel patterns and processes of normal contralateral targeting were identified, as well as distinct periods of region-specific activitydependent and -independent axonal exuberance. Contralateral callosal targeting was also shown to be not just dependent on neuronal activity, but rather a balance of spatially symmetric activity between the two cortical hemispheres. The molecular mechanisms underlying activity-dependent and -independent stages of contralateral callosal targeting were also investigated, and a novel technique to extract RNA from an electroporated population of cell bodies and/or their callosal axons was developed to facilitate this study in the future.These results constitute fundamental insights into the process of contralateral callosal targeting, as well as some of the mechanisms that may lead to its disruption. This work provides solid foundations for future studies to build upon, and may ultimately help us to better understand subtle human disorders of neuronal connectivity.3

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Gli3 Controls Corpus Callosum Formation by Positioning Midline Guideposts During Telencephalic Patterning

Cited by 35 publications

References 69 publications

The tumor suppressor Nf2 regulates corpus callosum development by inhibiting the transcriptional coactivator Yap

The tumor suppressor Nf2 regulates corpus callosum development by inhibiting the transcriptional coactivator Yap

Le cil primaire, orchestrateur de la morphogenèse cérébrale

Contralateral targeting of the corpus callosum

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