Cux2 serves as a novel lineage marker of granule cell layer neurons from the rhombic lip in mouse and chick embryos

Sonic hedgehog promotes proliferation of developing cerebellar granule cells. As sonic hedgehog is expressed in the cerebellum throughout life it is not clear why proliferation occurs only in the early postnatal period and only in the external granule cell layer. We asked whether heparan sulfate proteoglycans might regulate sonic hedgehog-induced proliferation and thereby contribute to the specialized proliferative environment of the external granule cell layer. We identified a conserved sequence within sonic hedgehog that is essential for binding to heparan sulfate proteoglycans, but not for binding to the receptor patched. Sonic hedgehog interactions with heparan sulfate proteoglycans promote maximal proliferation of postnatal day 6 granule cells. By contrast, proliferation of less mature granule cells is not affected by sonic hedgehog-proteoglycan interactions. The importance of proteoglycans for proliferation increases during development in parallel with increasing expression of the glycosyltransferase genes, exostosin 1 and exostosin 2. These data suggest that heparan sulfate proteoglycans, synthesized by exostosins, may be critical determinants of granule cell proliferation.

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BDNF stimulates migration of cerebellar granule cells

Development ◽

10.1242/dev.129.6.1435 ◽

2002 ◽

Vol 129 (6) ◽

pp. 1435-1442 ◽

Cited By ~ 3

Author(s):

Paul R. Borghesani ◽

Jean Michel Peyrin ◽

Robyn Klein ◽

Joshua Rubin ◽

Alexandre R. Carter ◽

...

Keyword(s):

Granule Cell ◽

Granule Cells ◽

Cerebellar Granule Cells ◽

Cell Layer ◽

Time Lapse ◽

Granule Cell Layer ◽

Boyden Chamber ◽

Cerebellar Granule ◽

Proliferative Zone ◽

On Line

During development of the nervous system, neural progenitors arise in proliferative zones, then exit the cell cycle and migrate away from these zones. Here we show that migration of cerebellar granule cells out of their proliferative zone, the external granule cell layer (EGL), is impaired in Bdnf–/– mice. The reason for impaired migration is that BDNF directly and acutely stimulates granule cell migration. Purified Bdnf–/– granule cells show defects in initiation of migration along glial fibers and in Boyden chamber assays. This phenotype can be rescued by exogenous BDNF. Using time-lapse video microscopy we find that BDNF is acutely motogenic as it stimulates migration of individual granule cells immediately after addition. The stimulation of migration reflects both a chemokinetic and chemotactic effect of BDNF. Collectively, these data demonstrate that BDNF is directly motogenic for granule cells and provides a directional cue promoting migration from the EGL to the internal granule cell layer (IGL). Movies available on-line

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Dentate Gyrus Immaturity in Schizophrenia

The Neuroscientist ◽

10.1177/1073858418824072 ◽

2019 ◽

Vol 25 (6) ◽

pp. 528-547 ◽

Cited By ~ 5

Author(s):

Ayda Tavitian ◽

Wei Song ◽

Hyman M. Schipper

Keyword(s):

Animal Models ◽

Dentate Gyrus ◽

Granule Cell ◽

Cell Layer ◽

Current Theory ◽

Position Paper ◽

Granule Cell Layer ◽

Molecular Profile ◽

Rodent Models

Hippocampal abnormalities have been heavily implicated in the pathophysiology of schizophrenia. The dentate gyrus of the hippocampus was shown to manifest an immature molecular profile in schizophrenia subjects, as well as in various animal models of the disorder. In this position paper, we advance a hypothesis that this immature molecular profile is accompanied by an identifiable immature morphology of the dentate gyrus granule cell layer. We adduce evidence for arrested maturation of the dentate gyrus in the human schizophrenia-affected brain, as well as multiple rodent models of the disease. Implications of this neurohistopathological signature for current theory regarding the development of schizophrenia are discussed.

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Dynamic properties of sensory stimulation evoked responses in mouse cerebellar granule cell layer and molecular layer

Neuroscience Letters ◽

10.1016/j.neulet.2014.11.037 ◽

2015 ◽

Vol 585 ◽

pp. 114-118 ◽

Cited By ~ 9

Author(s):

Yan-Hua Bing ◽

Guang-Jian Zhang ◽

Lei Sun ◽

Chun-Ping Chu ◽

De-Lai Qiu

Keyword(s):

Granule Cell ◽

Cell Layer ◽

Dynamic Properties ◽

Molecular Layer ◽

Sensory Stimulation ◽

Cerebellar Granule Cell ◽

Granule Cell Layer ◽

Evoked Responses ◽

Cerebellar Granule

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A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1611431114 ◽

2016 ◽

Vol 114 (1) ◽

pp. 125-130 ◽

Cited By ~ 38

Author(s):

Joel S. Benjamin ◽

Genay O. Pilarowski ◽

Giovanni A. Carosso ◽

Li Zhang ◽

David. L. Huso ◽

...

Keyword(s):

Intellectual Disability ◽

Mouse Model ◽

Ketogenic Diet ◽

Granule Cell ◽

Dietary Intervention ◽

Cell Layer ◽

Chromatin Accessibility ◽

Granule Cell Layer ◽

Kabuki Syndrome ◽

Beta Hydroxybutyrate

Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/βGeo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/βGeo mice modulates H3ac and H3K4me3 in the granule cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/βGeo mice; similar effects on neurogenesis were observed on exogenous administration of beta-hydroxybutyrate. These data suggest that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders.

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