Conditional Deletion of PDK1 in the Forebrain Causes Neuron Loss and Increased Apoptosis during Cortical Development

Xu, Congcong; Yu, Liu; Hou, Jinxing; Jackson, Rosemary J.; Wang, He; Huang, Ching-Hui; Liu, Tingting; Wang, Qihui; Zou, Xiaochuan; Morris, Richard G.; Spires‐Jones, Tara L.; Yang, Zhongzhou; Yin, Zhenyu; Xu, Yun; Chen, Guiquan

doi:10.3389/fncel.2017.00330

Cited by 21 publications

(30 citation statements)

References 38 publications

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“…Previous studies have demonstrated that the phosphorylation of AKT at Thr308 by PDK1 is essential for its activation [64,65]. Loss of Pdk1 results in decreased AKT activity, consequently leading to an increased apoptosis of excitatory neurons at postnatal rather than embryonic stages [30]. Here, we first examined total AKT level in the ventral telencephalon and observed no significant differences at E16.5 ( Fig.…”

Section: Decreased Activity Of Akt-gsk3β Signaling Pathway After Pdk1mentioning

confidence: 73%

“…Here considering the Dlx5/6-Cre is a powerful tool to delete genes in SVZ progenitors in the ventral telencephalon [14], and the Pdk1 fl/fl line has been employed to disrupt Pdk1 in several studies [30][31][32], combined with the result of Quantitative real-time PCR, Pdk1 could be considered to be efficiently deleted. Most Pdk1 cKO mice died shortly after birth, with a very small number surviving to P15.…”

Section: Loss Of Pdk1 Results In a Severe Reduction In Cortical Intermentioning

confidence: 99%

“…Deletion of Pdk1 in the PDK1 serves as an antiapoptotic factor in a variety of cell types, such as cancer cells, endothelial cells, and skeletal muscle cells [28,61,62,[77][78][79][80][81]. Recently, it was reported that the ablation of Pdk1 in the dorsal telencephalon leads to the increased apoptosis of cortical excitatory neurons at postnatal rather than embryonic stages [30,31]. Here, we found that during cortical interneuron development apoptosis occurred in the embryonic stages and lasted to the postnatal stages, resulting in a dramatical reduction in cortical interneurons, including MGE-derived SST + and PV + interneurons and the CGE-derived PROX1 + subtypes.…”

Section: Discussionmentioning

confidence: 99%

“…PDK1, the key downstream effector of PI3K signaling that is activated by various extracellular stimuli, is involved in many biological processes, such as cell proliferation and growth, neural differentiation, cell migration, cell polarization and cell survival [23][24][25][26][27][28]. Conditional deletion of Pdk1 results in increased apoptosis and migration defects in excitatory neurons [29,30]. Previously, we reported that PDK1 controls the transition of apical progenitors to basal progenitors through regulating asymmetric cell division, causing subsequent increased cell proliferation and neural output in the developing cortex [31].…”

Section: Introductionmentioning

confidence: 99%

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PDK1 regulates the survival of the developing cortical interneurons

2020

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Inhibitory interneurons are critical for maintaining the excitatory/inhibitory balance. During the development cortical interneurons originate from the ganglionic eminence and arrive at the dorsal cortex through two tangential migration routes. However, the mechanisms underlying the development of cortical interneurons remain unclear. 3-Phosphoinositide-dependent protein kinase-1 (PDK1) has been shown to be involved in a variety of biological processes, including cell proliferation and migration, and plays an important role in the neurogenesis of cortical excitatory neurons. However, the function of PDK1 in interneurons is still unclear. Here, we reported that the disruption of Pdk1 in the subpallium achieved by crossing the Dlx5/6-Cre-IRES-EGFP line with Pdk1 fl/fl mice led to the severely increased apoptosis of immature interneurons, subsequently resulting in a remarkable reduction in cortical interneurons. However, the tangential migration, progenitor pools and cell proliferation were not affected by the disruption of Pdk1. We further found the activity of AKT-GSK3β signaling pathway was decreased after Pdk1 deletion, suggesting it might be involved in the regulation of the survival of cortical interneurons. These results provide new insights into the function of PDK1 in the development of the telencephalon.

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Section: Decreased Activity Of Akt-gsk3β Signaling Pathway After Pdk1mentioning

confidence: 73%

Section: Loss Of Pdk1 Results In a Severe Reduction In Cortical Intermentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PDK1 regulates the survival of the developing cortical interneurons

2020

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“…Western blotting was conducted using a protocol described previously [ 3 , 33 ]. Normalized volumes of samples (40 μg total protein) were resolved in 10% 15-well SDS-PAGE gels (invitrogen), transferred to nitrocellulose membrane.…”

Section: Methodsmentioning

confidence: 99%

Dexamethasone does not ameliorate gliosis in a mouse model of neurodegenerative disease

Zou

Hou

et al. 2020

Biochemistry and Biophysics Reports

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Prolonged neuroinflammation is a driving force for neurodegenerative disease, and agents against inflammatory responses are regarded as potential treatment strategies. Here we aimed to evaluate the prevention effects on gliosis by dexamethasone (DEX), an anti-inflammation drug. We used DEX to treat the nicastrin conditional knockout (cKO) mouse, a neurodegenerative mouse model. DEX (10 mg/kg) was given to 2.5-month-old nicastrin cKO mice, which have not started to display neurodegeneration and gliosis, for 2 months. Immunohistochemistry (IHC) and Western blotting techniques were used to detect changes in neuroinflammatory responses. We found that activation of glial fibrillary acidic protein (GFAP) positive or ionized calcium binding adapter molecule1 (Iba1) positive cells was not inhibited in nicastrin cKO mice treated with DEX as compared to those treated with saline. These data suggest that DEX does not prevent or ameliorate gliosis in a neurodegenerative mouse model when given prior to neuronal or synaptic loss.

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Neural Tissue‐Like, not Supraphysiological, Electrical Conductivity Stimulates Neuronal Lineage Specification through Calcium Signaling and Epigenetic Modification

Li,

Ji,

Meng

et al. 2024

Advanced Science

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Electrical conductivity is a pivotal biophysical factor for neural interfaces, though optimal values remain controversial due to challenges isolating this cue. To address this issue, conductive substrates made of carbon nanotubes and graphene oxide nanoribbons, exhibiting a spectrum of conductivities from 0.02 to 3.2 S m−1, while controlling other surface properties is designed. The focus is to ascertain whether varying conductivity in isolation has any discernable impact on neural lineage specification. Remarkably, neural‐tissue‐like low conductivity (0.02–0.1 S m−1) prompted neural stem/progenitor cells to exhibit a greater propensity toward neuronal lineage specification (neurons and oligodendrocytes, not astrocytes) compared to high supraphysiological conductivity (3.2 S m−1). High conductivity instigated the apoptotic process, characterized by increased apoptotic fraction and decreased neurogenic morphological features, primarily due to calcium overload. Conversely, cells exposed to physiological conductivity displayed epigenetic changes, specifically increased chromatin openness with H3acetylation (H3ac) and neurogenic‐transcription‐factor activation, along with a more balanced intracellular calcium response. The pharmacological inhibition of H3ac further supported the idea that such epigenetic changes might play a key role in driving neuronal specification in response to neural‐tissue‐like, not supraphysiological, conductive cues. These findings underscore the necessity of optimal conductivity when designing neural interfaces and scaffolds to stimulate neuronal differentiation and facilitate the repair process.

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Conditional Deletion of PDK1 in the Forebrain Causes Neuron Loss and Increased Apoptosis during Cortical Development

Cited by 21 publications

References 38 publications

PDK1 regulates the survival of the developing cortical interneurons

PDK1 regulates the survival of the developing cortical interneurons

Dexamethasone does not ameliorate gliosis in a mouse model of neurodegenerative disease

Neural Tissue‐Like, not Supraphysiological, Electrical Conductivity Stimulates Neuronal Lineage Specification through Calcium Signaling and Epigenetic Modification

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