Cell death and neurodegeneration in the postnatal development of cerebellar vermis in normal and Reeler mice

Castagna, Claudia; Merighi, Adalberto

doi:10.1016/j.aanat.2016.01.010

Cited by 21 publications

(25 citation statements)

References 75 publications

(74 reference statements)

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“…The two forms of programmed cell death, autophagic cell death and apoptosis, are not mutually exclusive and may contribute to oncogenesis and mortality (14). Traditionally, autophagic cell death is characterized by the formation of autophagic vacuoles, and regulation of the caspase family performs diversified roles in pathophysiology and physiology in various cell types (11,15).…”

Section: Discussionmentioning

confidence: 99%

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

et al. 2016

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Previous studies have demonstrated that the chronic administration of valproic acid (VPA) suppresses angiogenesis in vivo; however, the mechanisms implicated in VPA-induced autophagy remain unclear. The current study aimed to assess VPA-induced autophagy in three prostate cancer cell lines (PC3, DU145 and LNCaP), in addition to analyzing the Akt/mammalian target of rapamycin (mTOR) signal pathway. Prostate cancer cell lines were cultured with various doses of VPA. Cell cycle was analyzed using flow cytometry, and autophagy markers [1A/1B-light chain 3 (LC3)-II and Beclin-1] were examined using transmission electron microscopy, fluorescent microscopy and western blotting. Activation of the Akt/mTOR signal pathway was also assessed by western blotting. The results demonstrated that VPA induced autophagosomes and suppressed the Akt/mTOR signal pathway. This was confirmed by detection of increased LC3-II and Beclin-1 in VPA-treated cells compared with untreated controls. Phosphorylated forms of Akt (PC3, P=0.048; DU145, P=0.045; LNCaP, P=0.039) and mTOR (PC3, P=0.012; DU145, P=0.41; LNCaP, P=0.35) were significantly reduced following VPA treatment. These results suggest that VPA may function as a histone deacetylase inhibitor, suppressing the growth of prostate cancer cells by modulating autophagy pathways, including inhibition of the Akt/mTOR pathway. Further experiments are required to determine the significance of all involved pathways regarding VPA-induced growth inhibition.

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Section: Discussionmentioning

confidence: 99%

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

et al. 2016

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“…Therefore, beside the well-defined consequences onto neuronal migration, the lack of Reln also caused a calculable deficit in neuronal expansion. Ultrastructurally, the cerebellar neurons underwent several different forms of programmed cell death during postnatal development and the deficit of Reln affected the kind and grade of neuronal death [94].…”

Section: Lissencephaly 2 A) Humansmentioning

confidence: 99%

The Reeler Mouse: A Translational Model of Human Neurological Conditions, or Simply a Good Tool for Better Understanding Neurodevelopment?

Lossi

Castagna

Granato

et al. 2019

JCM

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The first description of the Reeler mutation in mouse dates to more than fifty years ago, and later, its causative gene (reln) was discovered in mouse, and its human orthologue (RELN) was demonstrated to be causative of lissencephaly 2 (LIS2) and about 20% of the cases of autosomal-dominant lateral temporal epilepsy (ADLTE). In both human and mice, the gene encodes for a glycoprotein referred to as reelin (Reln) that plays a primary function in neuronal migration during development and synaptic stabilization in adulthood. Besides LIS2 and ADLTE, RELN and/or other genes coding for the proteins of the Reln intracellular cascade have been associated substantially to other conditions such as spinocerebellar ataxia type 7 and 37, VLDLR-associated cerebellar hypoplasia, PAFAH1B1-associated lissencephaly, autism, and schizophrenia. According to their modalities of inheritances and with significant differences among each other, these neuropsychiatric disorders can be modeled in the homozygous (reln −/− ) or heterozygous (reln +/− ) Reeler mouse. The worth of these mice as translational models is discussed, with focus on their construct and face validity. Description of face validity, i.e., the resemblance of phenotypes between the two species, centers onto the histological, neurochemical, and functional observations in the cerebral cortex, hippocampus, and cerebellum of Reeler mice and their human counterparts. mutations of the RELN gene were linked to a form of lissencephaly with cerebellar hypoplasia (LCH) [9], with associated findings suggested that RELN was linked to some neuropsychiatric conditions [10], and RELN was demonstrated to be reduced in the cerebellum of autistic patients after Western blotting and immunodetection [11].Determining a good translational mouse model for a neuropsychiatric condition needs construct, predictive, and face validity [12]. Rigorously, construct validity only relates to transgenic mice, but, in a broader definition, it also comprehends the syndromic models and the spontaneous DNA mutations linked to the phenotype under study. In other words, this factor defines the similarity of the disease between the mouse and the human disorder in terms of the causal gene(s) as e.g., deducted from gene association and linkage analysis. As mentioned above, LCH is a human monogenic condition caused by a mutation in RELN. Therefore, the Reeler mouse fully meets the criterion of construct validity for the condition. There is also evidence for genetics to be associated with the etiology of several neuropsychiatric conditions, such as autism and schizophrenia, but, as the result of their multidimensional clinical symptoms, causal gene(s), if any, persist to be undiscovered [13]. Nonetheless, there are numerous genes associated with the human autistic pathology after analysis of Mendelian disorders (syndromes), rare mutations, or association studies; see e.g., [14].Predictive validity, i.e., the similarity of the response to cures in humans and mice is difficult to establish, in the nonexistence of a re...

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“…The density of granule cells also was lower compared to No DT and P1- PC-DTR P30 mice (Figure4_supplement 4F). Interestingly, PCs in P5- PC-DTR mice had a larger soma (Figure 4D) and longer primary and secondary dendrites (Figure 4E) compared to No DT or P1- PC-DTR mice, a cellular phenotype observed in some mouse mutants with PC loss (Castagna, Merighi, & Lossi, 2016). Furthermore, compared to controls, the percentage of PCs that survived in P5- PC-DTR animals (∼66% of No DT controls) did not match the percentage of granule cells that were produced (∼81% of No DT controls).…”

Section: Resultsmentioning

confidence: 97%

Age-dependent dormant resident progenitors are stimulated by injury to regenerate Purkinje neurons

Bayin

Wojcinski

Mourton

et al. 2018

Preprint

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25Outside of the neurogenic niches of the brain, postmitotic neurons have not been 26 found to undergo efficient regeneration. Here we demonstrate that Purkinje cells 27 (PCs), which are born at midgestation and are crucial for both development and 28 function of cerebellar circuits, are rapidly and fully regenerated following their 29 ablation at birth. New PCs are produced by a previously unidentified progenitor 30 population and support normal cerebellum development. The number of PC 31 progenitors and their regenerative capacity, however, diminish soon after birth, 32 and consequently PCs are poorly replenished when ablated at postnatal day 5. 33Nevertheless, the PC-depleted cerebella reach a normal size by increasing cell 34 size, but scaling of neuron types is disrupted and cerebellar function is impaired. 35Our findings thus provide a new paradigm in the field of neuron regeneration by 36 identifying a unipotent neural progenitor that buffers against perinatal brain injury 37 in a stage-dependent process.

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Cell death and neurodegeneration in the postnatal development of cerebellar vermis in normal and Reeler mice

Cited by 21 publications

References 75 publications

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

The Reeler Mouse: A Translational Model of Human Neurological Conditions, or Simply a Good Tool for Better Understanding Neurodevelopment?

Age-dependent dormant resident progenitors are stimulated by injury to regenerate Purkinje neurons

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