F3/contactin and TAG1 play antagonistic roles in the regulation of sonic hedgehog-induced cerebellar granule neuron progenitor proliferation

Xenaki, Dia; Martin, Indira B.; Yoshida, Lynn; Ohyama, Katsumi; Gennarini, Gianfranco; Grumet, Martin; Sakurai, Takeshi; Furley, Andrew J.

doi:10.1242/dev.051912

Cited by 61 publications

(59 citation statements)

References 62 publications

(105 reference statements)

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“…4). Likewise, in contrast to its role in the cortical ventricular zone (Bizzoca et al, 2012), the lamina-specific expression of F3/contactin in the EGL suppresses Shh-dependent proliferation and is antagonised by its binding partner Tag1 (Xenaki et al, 2011), the deletion of which leads to ectopic subpial granule cell clusters in adult mice. Correspondingly, premature misexpression of F3/contactin attenuates granule cell progenitor proliferation (Bizzoca et al, 2003).…”

Section: Balancing Proliferation and Differentiation In The Externalmentioning

confidence: 99%

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

Green²,

2014

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The cerebellum is a pre-eminent model for the study of neurogenesis and circuit assembly. Increasing interest in the cerebellum as a participant in higher cognitive processes and as a locus for a range of disorders and diseases make this simple yet elusive structure an important model in a number of fields. In recent years, our understanding of some of the more familiar aspects of cerebellar growth, such as its territorial allocation and the origin of its various cell types, has undergone major recalibration. Furthermore, owing to its stereotyped circuitry across a range of species, insights from a variety of species have contributed to an increasingly rich picture of how this system develops. Here, we review these recent advances and explore three distinct aspects of cerebellar development -allocation of the cerebellar anlage, the significance of transit amplification and the generation of neuronal diversity -each defined by distinct regulatory mechanisms and each with special significance for health and disease.

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Section: Balancing Proliferation and Differentiation In The Externalmentioning

confidence: 99%

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

Green²,

2014

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“…The IgSF CAMs Contactin1 and Contactin2 were not only shown to guide axons (see above) but also to affect neurogenesis in the cerebellum, the cortex, and also the adult hippocampus (Bizzoca et al 2003 andMa et al, 2008;Xenaki et al, 2011;Puzzo et al, 2013). In order to understand the link between neural development and neurodevelopmental disorders, we will need to take a more integrative look at the role of molecules and mechanisms in neural circuit formation.…”

Section: Syncams As Axon Guidance Molecules In the Pnsmentioning

confidence: 99%

SynCAMs – From axon guidance to neurodevelopmental disorders

Frei

Stoeckli

2017

Molecular and Cellular Neuroscience

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Many cell adhesion molecules are located at synapses but only few of them can be considered synaptic cell adhesion molecules in the strict sense. Besides the Neurexins and Neuroligins, the LRRTMs (leucine rich repeat transmembrane proteins) and the SynCAMs/CADMs can induce synapse formation when expressed in non-neuronal cells and therefore are true synaptic cell adhesion molecules. SynCAMs (synaptic cell adhesion molecules) are a subfamily of the immunoglobulin superfamily of cell adhesion molecules. As suggested by their name, they were first identified as cell adhesion molecules at the synapse which were sufficient to trigger synapse formation. They also contribute to myelination by mediating axon-glia cell contacts. More recently, their role in earlier stages of neural circuit formation was demonstrated, as they also guide axons both in the peripheral and in the central nervous system. Mutations in SynCAM genes were found in patients diagnosed with autism spectrum disorders. The diverse functions of SynCAMs during development suggest that neurodevelopmental disorders are not only due to defects in synaptic plasticity. Rather, early steps of neural circuit formation are likely to contribute. Many cell adhesion molecules are located at synapses but only few of them can be considered synaptic cell adhesion molecules in the strict sense. Besides the Neurexins and Neuroligins, the LRRTMs (leucine rich repeat transmembrane proteins) and the SynCAMs/CADMs can induce synapse formation when expressed in non-neuronal cells and therefore are true synaptic cell adhesion molecules. SynCAMs (synaptic cell adhesion molecules) are a subfamily of the immunoglobulin superfamily of cell adhesion molecules. As suggested by their name, they were first identified as cell adhesion molecules at the synapse which were sufficient to trigger synapse formation. They also contribute to myelination by mediating axon-glia cell contacts. More recently, their role in earlier stages of neural circuit formation was demonstrated, as they also guide axons both in the peripheral and in the central nervous system. Mutations in SynCAM genes were found in patients diagnosed with autism spectrum disorders. The diverse functions of SynCAMs during development suggest that neurodevelopmental disorders are not only due to defects in synaptic plasticity. Rather, early steps of neural circuit formation are likely to contribute.

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“…Rios et al (2004) propose a model in which BMPs antagonize SHH signaling to promote GCP differentiation over proliferation. More recently, Xenaki et al (2011) have shown that two cell adhesion proteins of the contactin (Cntn) family, Tag-1 (Cntn2) and F3 (Cntn1), are involved in regulating GCP proliferation in the EGL. F3 was shown to promote granule cell differentiation in the EGL by suppressing SHH's positive regulation of GCP proliferation, while TAG-1 helps sustain proliferation (Xenaki et al, 2011).…”

Section: Shox2 Is Important For Maintaining Shh Expression Levels Inmentioning

confidence: 99%

“…More recently, Xenaki et al (2011) have shown that two cell adhesion proteins of the contactin (Cntn) family, Tag-1 (Cntn2) and F3 (Cntn1), are involved in regulating GCP proliferation in the EGL. F3 was shown to promote granule cell differentiation in the EGL by suppressing SHH's positive regulation of GCP proliferation, while TAG-1 helps sustain proliferation (Xenaki et al, 2011). When F3/contactin expression is driven by Tag-1 regulatory sequences, the cerebellum is reduced in size during the first two postnatal weeks of development, presumably because of a reduction in the number of GCPs present in the EGL, and ultimately results in a thinner IGL (Bizzoca et al, 2003).…”

Section: Shox2 Is Important For Maintaining Shh Expression Levels Inmentioning

confidence: 99%

“…Disruption of the balance between these signals can result in medulloblastoma due to the constant activation of the SHH signal and resulting uncontrolled GCP proliferation (Grimmer and Weiss, 2008;Zhao et al, 2008). Despite the pivotal function of SHH in cerebellar development, the upstream regulators that establish and/or maintain the Shh expression pattern in this brain region are only just starting to be uncovered (Gold et al, 2003;Wang et al, 2011;Xenaki et al, 2011). In addition, while a number of studies have demonstrated that BMP signaling can antagonize SHH-mediated GCP proliferation (Grimmer and Weiss, 2008;Rios et al, 2004), the signals responsible for the correct timing and proper balance of cerebellar GCP proliferation and granule cell differentiation have yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Mice lacking the transcription factor SHOX2 display impaired cerebellar development and deficits in motor coordination

Rosin

McAllister

Dyck

et al. 2015

Developmental Biology

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Purkinje cells of the developing cerebellum secrete the morphogen sonic hedgehog (SHH), which is required to maintain the proliferative state of granule cell precursors (GCPs) prior to their differentiation and migration to form the internal granule layer (IGL). Despite a wealth of knowledge regarding the function of SHH during cerebellar development, the upstream regulators of Shh expression during this process remain largely unknown. Here we report that the murine short stature homeobox 2 (Shox2) gene is required for normal Shh expression in dorsal-residing Purkinje cells. Using two different Cre drivers, we show that elimination of Shox2 in the brain results in developmental defects in the inferior colliculus and cerebellum. Specifically, loss of Shox2 in the cerebellum results in precocious differentiation and migration of GCPs from the external granule layer (EGL) to the IGL. This correlates with premature bone morphogenetic protein 4 (Bmp4) expression in granule cells of the dorsal cerebellum. The size of the neonatal cerebellum is reduced in Shox2-mutant animals, which is consistent with a reduction in the number of GCPs present in the EGL, and could account for the smaller vermis and thinner IGL present in adult Shox2mutants. Shox2-mutant mice also display reduced exploratory activity, altered gait and impaired motor coordination. Our findings are the first to show a role for Shox2 in brain development. We provide evidence that Shox2 plays an important role during cerebellar development, perhaps to maintain the proper balance of Shh and Bmp expression levels in the dorsal vermis, and demonstrate that in the absence of Shox2, mice display both cerebellar impairments and deficits in motor coordination, ultimately highlighting the importance of Shox2 in the cerebellum.

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F3/contactin and TAG1 play antagonistic roles in the regulation of sonic hedgehog-induced cerebellar granule neuron progenitor proliferation

Cited by 61 publications

References 62 publications

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

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

SynCAMs – From axon guidance to neurodevelopmental disorders

Mice lacking the transcription factor SHOX2 display impaired cerebellar development and deficits in motor coordination

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