Laminating the hippocampus

Förster, Eckart; Zhao, Shanting; Frotscher, Michael

doi:10.1038/nrn1882

Cited by 218 publications

(179 citation statements)

References 111 publications

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“…Specifically, new born neurons proliferate in the subgranular zone of the dentate gyrus, from which they migrate either into the granule cell layer or hilar region of the dentate gyrus and form functional connections. 17 Therefore, these data raise the intriguing possibility that the loss of proper neurogenesis in RanBP9 transgenic brains might at least in part account for the observed synapse loss seen within the SL of CA3 and hilus/IML of the dentate gyrus. Furthermore, the observation that RanBP9 transgenic mice are severely impaired in hippocampus-dependent spatial memory tasks functionally underscores the neuroinflammation, neurodegeneration, and synaptic loss seen in the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

et al. 2012

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Neurodegeneration associated with amyloid b (Ab) peptide accumulation, synaptic loss, neuroinflammation, tauopathy, and memory impairments encompass the pathophysiological features of Alzheimer's disease (AD). We previously reported that the scaffolding protein RanBP9, which is overall increased in brains of AD patients, simultaneously promotes Ab generation and focal adhesion disruption by accelerating the endocytosis of amyloid precursor protein (APP) and b1-integrin, respectively. Here, we show that RanBP9 protein levels are increased by fourfold in FAD mutant APP transgenic mice. Accordingly, RanBP9 transgenic mice demonstrate significantly increased synapse loss, neurodegeneration, gliosis, and spatial memory deficits. RanBP9 overexpression promotes apoptosis and potentiates Ab-induced neurotoxicity independent of its capacity to promote Ab generation. Conversely, RanBP9 reduction by siRNA or gene dosage mitigates Ab-induced neurotoxicity. Importantly, RanBP9 activates/dephosphorylates cofilin, a key regulator of actin dynamics and mitochondria-mediated apoptosis, and siRNA knockdown of cofilin abolishes both Ab and RanBP9-induced apoptosis. These findings implicate the RanBP9-cofilin pathway as critical therapeutic targets not only for stemming Ab generation but also antagonizing Ab-induced neurotoxicity. Cell Death and Differentiation (2012) 19, 1413-1423; doi:10.1038/cdd.2012.14; published online 24 February 2012Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulations of the amyloid b (Ab) -peptide and hyperphosphorylated tau in senile plaques and neurofibrillary tangles, respectively. Ab is a neurotoxic peptide derived from b-and g-secretase cleavages of the amyloid precursor protein (APP) and is thought to be a critical early player in AD pathogenesis. 1 In addition to the accumulation of Ab and tau, abnormalities in the actin cytoskeleton are detected earlier during the course of AD and other neurodegenerative diseases. 2 Indeed, it has been demonstrated that Ab can induce actin/cofilin pathology associated with hyperphosphorylated tau in primary neurons and in vivo. [3][4][5] We recently demonstrated that the scaffolding protein RanBP9 interacts with the cytoplasmic tails of LRP, APP, and BACE1, and functions as a scaffold upon which APP is brought together with BACE1 and LRP. Such interactions of RanBP9 promote the endocytosis of APP and strongly increase BACE1 cleavage of APP to generate Ab in vitro and in vivo. 6,7 Conversely, siRNA knockdown of RanBP9 reduces BACE1 cleavage of APP and Ab generation, indicating that endogenous RanBP9 normally functions in this capacity. 6 In addition, a 60-kD proteolytic fragment of RanBP9 is increased by more than sixfold in brains of AD patients, and this fragment potentiates Ab generation via BACE1 processing of APP. 8 In addition to promoting Ab generation by accelerating APP endocytosis, RanBP9 also potently disrupts integrin-dependent focal adhesion signaling and assembly by accelerating b1-integrin and LRP endocytosis. 9 In th...

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Section: Discussionmentioning

confidence: 99%

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

et al. 2012

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“…In the region of the dentate gyrus, the Prox1 ϩ cells of the neuroepithelium joined the dentate migratory stream (DMS) and had migrated dorsally towards the anlage of the dentate gyrus, near the pial surface (small box in Fig. 3D) (reviewed in Forster et al, 2006). Prox1-positive cells were detected also at E16.5 in the SVZ of the neocortex (Fig.…”

Section: Prox1 Expression In the Svz Of The E165 Cortexmentioning

confidence: 96%

Prox1 expression patterns in the developing and adult murine brain

Lavado

Oliver

2006

Developmental Dynamics

144

124

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Prox1, a homeobox gene related to the Drosophila gene prospero, is necessary for retina, lens, liver, pancreas, and lymphatics development. However, not much is yet known about Prox1 expression during central nervous system development. Here we provide a detailed analysis of Prox1 mRNA and protein expression during prenatal and postnatal murine brain development. Prenatally, Prox1 is expressed in the subventricular zone or in early differentiating regions of the brain. At these stages, Prox1 mRNA, but not Prox1 protein, was also detected in several regions of the prethalamus and hypothalamus. At an early postnatal stage, Prox1 expression is mainly detected in several nuclei of the thalamus, the cerebellum, and the hippocampus. In adulthood, Prox1 expression remains only in the hippocampus and cerebellum. These complex patterns of expression suggest that Prox1 activity is differentially required during brain development and adulthood. Developmental Dynamics 236:518 -524, 2007.

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“…In the absence of Wnt3a from the hem, or loss of Wnt signaling component LEF1 or β-catenin in the presumptive anlage, the hippocampal primordium fails to develop (5,6). Furthermore, a number of other factors have been found to participate in the initial phase of hippocampal development by regulating Wnt signaling, including FOXG1, FGF, BMPs, Gli3, and EMX1/2 (7,8). However, little is known about how hippocampal field identities are specified and how differential cell fate decisions in the hippocampal and transitional neocortex primordia are developmentally controlled.…”

mentioning

confidence: 99%

Zbtb20 is essential for the specification of CA1 field identity in the developing hippocampus

Xie¹,

Ma²,

Wyatt³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

110

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The development of hippocampal circuitry depends on the proper assembly of correctly specified and fully differentiated hippocampal neurons. Little is known about factors that control the hippocampal specification. Here, we show that zinc finger protein Zbtb20 is essential for the specification of hippocampal CA1 field identity. We found that Zbtb20 expression was initially activated in the hippocampal anlage at the onset of corticogenesis, and persisted in immature hippocampal neurons. Targeted deletion of Zbtb20 in mice did not compromise the progenitor proliferation in the hippocampal and adjacent transitional ventricular zone, but led to the transformation of the hippocampal CA1 field into a transitional neocortex-like structure, as evidenced by cytoarchitectural, neuronal migration, and gene expression phenotypes. Correspondingly, the subiculum was ectopically located adjacent to the CA3 in mutant. Although the field identities of the mutant CA3 and dentate gyrus (DG) were largely maintained, their projections were severely impaired. The hippocampus of Zbtb20 null mice was reduced in size, and exhibited increased apoptotic cell death during postnatal development. Our data establish an essential role of Zbtb20 in the specification of CA1 field identity by repressing adjacent transitional neocortex-specific fate determination.cell fate | neocortex | zinc finger transcription factor

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Laminating the hippocampus

Cited by 218 publications

References 111 publications

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

Prox1 expression patterns in the developing and adult murine brain

Zbtb20 is essential for the specification of CA1 field identity in the developing hippocampus

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