International Journal of Molecular Sciences

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4 pages, 184 KiB

Open AccessEditorial

Molecules Affecting Brain Development and Nervous System

by Kazuhiko Nakadate and Kiyoharu Kawakami

Int. J. Mol. Sci. 2023, 24(10), 8691; https://doi.org/10.3390/ijms24108691 - 12 May 2023

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Abstract

Brain development is the biological process through which neurons are produced [...] Full article

(This article belongs to the Special Issue Molecules Affecting Brain Development and Nervous System)

Research

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13 pages, 2130 KiB

Open AccessArticle

SOCS7-Derived BC-Box Motif Peptide Mediated Cholinergic Differentiation of Human Adipose-Derived Mesenchymal Stem Cells

by Hiroshi Kanno, Shutaro Matsumoto, Tetsuya Yoshizumi, Kimihiro Nakahara, Masamichi Shinonaga, Atsuhiko Kubo, Satoshi Fujii, Yasuyuki Ishizuka, Masaki Tanaka, Masamitsu Ichihashi and Hidetoshi Murata

Int. J. Mol. Sci. 2023, 24(3), 2786; https://doi.org/10.3390/ijms24032786 - 1 Feb 2023

Cited by 1 | Viewed by 1397

Abstract

Adipose-derived mesenchymal stem cells (ADMSCs) are a type of pluripotent somatic stem cells that differentiate into various cell types such as osteoblast, chondrocyte, and neuronal cells. ADMSCs as donor cells are used to produce regenerative medicines at hospitals and clinics. However, it has [...] Read more.

Adipose-derived mesenchymal stem cells (ADMSCs) are a type of pluripotent somatic stem cells that differentiate into various cell types such as osteoblast, chondrocyte, and neuronal cells. ADMSCs as donor cells are used to produce regenerative medicines at hospitals and clinics. However, it has not been reported that ADMSCs were differentiated to a specific type of neuron with a peptide. Here, we report that ADMSCs differentiate to the cholinergic phenotype of neurons by the SOCS7-derived BC-box motif peptide. At operations for patients with neurological disorders, a small amount of subcutaneous fat was obtained. Two weeks later, adipose-derived mesenchymal stem cells (ADMSCs) were isolated and cultured for a further 1 to 2 weeks. Flow cytometry analysis for characterization of ADMSCs was performed with CD73, CD90, and CD105 as positive markers, and CD14, CD31, and CD56 as negative markers. The results showed that cultured cells were compatible with ADMSCs. Immunocytochemical studies showed naïve ADMSCs immunopositive for p75NTR, RET, nestin, keratin, neurofilament-M, and smooth muscle actin. ADMSCs were suggested to be pluripotent stem cells. A peptide corresponding to the amino-acid sequence of BC-box motif derived from SOCS7 protein was added to the medium at a concentration of 2 μM. Three days later, immunocytochemistry analysis, Western blot analysis, ubiquitination assay, and electrophysiological analysis with patch cramp were performed. Immunostaining revealed the expression of neurofilament H (NFH), choline acetyltransferase (ChAT), and tyrosine hydroxylase (TH). In addition, Western blot analysis showed an increase in the expression of NFH, ChAT, and TH, and the expression of ChAT was more distinct than TH. Immunoprecipitation with JAK2 showed an increase in the expression of ubiquitin. Electrophysiological analysis showed a large holding potential at the recorded cells through path electrodes. The BC-box motif peptide derived from SOCS7 promoted the cholinergic differentiation of ADMSCs. This novel method will contribute to research as well as regenerative medicine for cholinergic neuron diseases. Full article

(This article belongs to the Special Issue Molecules Affecting Brain Development and Nervous System)

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22 pages, 6156 KiB

Open AccessArticle

Sucrose Consumption during Late Adolescence Impairs Adult Neurogenesis of the Ventral Dentate Gyrus without Inducing an Anxiety-like Behavior

by Karla Sánchez-Huerta, Rosaura Debbie Saldaña-Salinas, Pablo Edson Bustamante-Nieves, Adriana Jiménez, Alejandro Corzo-Cruz, Marina Martínez-Vargas, Rosalinda Guevara-Guzmán, Iván Velasco and Enrique Estudillo

Int. J. Mol. Sci. 2022, 23(22), 14176; https://doi.org/10.3390/ijms232214176 - 16 Nov 2022

Cited by 1 | Viewed by 2338

Abstract

Sucrose consumption impairs behavioral and cognitive functions that correlate with decreased neurogenesis in animal models. When consumed during early adolescence, this disaccharide promotes anxious and depressive behaviors, along with a reduction in the generation of new neurons in the dentate gyrus of the [...] Read more.

Sucrose consumption impairs behavioral and cognitive functions that correlate with decreased neurogenesis in animal models. When consumed during early adolescence, this disaccharide promotes anxious and depressive behaviors, along with a reduction in the generation of new neurons in the dentate gyrus of the hippocampus. Data concerning sucrose consumption during late adolescence are lacking, and the effect of sucrose intake on the ventral dentate gyrus of the hippocampus (which modulates anxiety and depression) remains elusive. Here, we tested whether sucrose intake during late adolescence causes anxiety or impaired neurogenesis in the ventral dentate gyrus. Rats did not display anxiety-like behaviors neither at the light–dark box test nor at the open field exploration. However, there was a significant increase in proliferative cells in the subgranular zone of the ventral dentate gyrus in rats exposed to sucrose (p < 0.05). This increased proliferation corresponded to neural stem cells (Radial Type 1 cells) in the group exposed to sucrose until adulthood but was not present in rats exposed to sucrose only during late adolescence. Remarkably, the phosphorylation of ERK1/2 kinases was increased in the hippocampi of rats exposed to sucrose only during late adolescence, suggesting that the increased proliferation in this group could be mediated by the MAPK pathway. On the other hand, although no differences were found in the number of immature granular neurons, we observed more immature granular neurons with impaired dendritic orientation in both groups exposed to sucrose. Finally, GAD65/67 and BCL2 levels did not change between groups, suggesting an unaltered hippocampal GABAergic system and similar apoptosis, respectively. This information provides the first piece of evidence of how sucrose intake, starting in late adolescence, impacts ventral dentate gyrus neurogenesis and contributes to a better understanding of the effects of this carbohydrate on the brain at postnatal stages. Full article

(This article belongs to the Special Issue Molecules Affecting Brain Development and Nervous System)

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13 pages, 7655 KiB

Open AccessArticle

Thyroxine Regulates the Opening of the Organ of Corti through Affecting P-Cadherin and Acetylated Microtubule

by Huimin Zhang, Le Xie, Sen Chen, Yue Qiu, Yu Sun and Weijia Kong

Int. J. Mol. Sci. 2022, 23(21), 13339; https://doi.org/10.3390/ijms232113339 - 1 Nov 2022

Cited by 2 | Viewed by 1432

Abstract

Different serum thyroxine levels may influence the morphology of the inner ear during development. A well-developed organ of Corti (OC) is considered to be critical to the function of hearing. In our study, we treated mice with triiodothyronine (T3) and found that the [...] Read more.

Different serum thyroxine levels may influence the morphology of the inner ear during development. A well-developed organ of Corti (OC) is considered to be critical to the function of hearing. In our study, we treated mice with triiodothyronine (T3) and found that the opening of the OC occurred sooner than in control mice. We also observed an increased formation of acetylated microtubules and a decrease in the adhesion junction molecule P-cadherin the during opening of the OC. Our investigation indicates that thyroxin affects P-cadherin expression and microtubule acetylation to influence the opening of the OC. Full article

(This article belongs to the Special Issue Molecules Affecting Brain Development and Nervous System)

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20 pages, 4741 KiB

Open AccessArticle

Distribution and Localization of Mahogunin Ring Finger 1 in the Mouse Central Nervous System

by Kazuhiko Nakadate and Kiyoharu Kawakami

Int. J. Mol. Sci. 2022, 23(16), 8956; https://doi.org/10.3390/ijms23168956 - 11 Aug 2022

Cited by 2 | Viewed by 1352

Abstract

Mahogunin ring finger 1 (MGRN1), an E3 ubiquitin, is involved in several physiological and neuropathological processes. Although mgrn1 mRNA is widely distributed in the central nervous system (CNS), detailed information on its cellular and subcellular localization is lacking and its physiological role remains [...] Read more.

Mahogunin ring finger 1 (MGRN1), an E3 ubiquitin, is involved in several physiological and neuropathological processes. Although mgrn1 mRNA is widely distributed in the central nervous system (CNS), detailed information on its cellular and subcellular localization is lacking and its physiological role remains unclear. In this study, we aimed to determine the distribution of MGRN1 in the mouse CNS using a newly produced antibody against MGRN1. We found that the MGRN1 protein was expressed in most neuronal cell bodies. An intense MGRN1 expression was also observed in the neuropil of the gray matter in different regions of the CNS, including the main olfactory bulb, cerebral cortex, caudate, putamen, thalamic nuclei, hypothalamic nuclei, medial eminence, superior colliculus, hippocampus, dentate gyrus, and spinal cord. Contrastingly, no MGRN1 expression was observed in glial cells. Double fluorescence and immunoelectron microscopic analyses revealed the intracellular distribution of MGRN1 in pre-synapses and near the outer membrane of the mitochondria in neurons. These findings indicate that MGRN1 is more widely expressed throughout the CNS; additionally, the intracellular expression of MGRN1 suggests that it may play an important role in synaptic and mitochondrial functions. Full article

(This article belongs to the Special Issue Molecules Affecting Brain Development and Nervous System)

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11 pages, 1000 KiB

Open AccessArticle

Nurr1 Is Not an Essential Regulator of BDNF in Mouse Cortical Neurons

by Mona Abdollahi and Margaret Fahnestock

Int. J. Mol. Sci. 2022, 23(12), 6853; https://doi.org/10.3390/ijms23126853 - 20 Jun 2022

Cited by 5 | Viewed by 1696

Abstract

Nurr1 and brain-derived neurotrophic factor (BDNF) play major roles in cognition. Nurr1 regulates BDNF in midbrain dopaminergic neurons and cerebellar granule cells. Nurr1 and BDNF are also highly expressed in the cerebral cortex, a brain area important in cognition. Due to Nurr1 and [...] Read more.

Nurr1 and brain-derived neurotrophic factor (BDNF) play major roles in cognition. Nurr1 regulates BDNF in midbrain dopaminergic neurons and cerebellar granule cells. Nurr1 and BDNF are also highly expressed in the cerebral cortex, a brain area important in cognition. Due to Nurr1 and BDNF tissue specificity, the regulatory effect of Nurr1 on BDNF in different brain areas cannot be generalized. The relationship between Nurr1 and BDNF in the cortex has not been investigated previously. Therefore, we examined Nurr1-mediated BDNF regulation in cortical neurons in activity-dependent and activity-independent states. Mouse primary cortical neurons were treated with the Nurr1 agonist, amodiaquine (AQ). Membrane depolarization was induced by KCl or veratridine and reversed by nimodipine. AQ and membrane depolarization significantly increased Nurr1 (p < 0.001) and BDNF (p_AQ < 0.001, p_KCl < 0.01) as assessed by real-time qRT-PCR. However, Nurr1 knockdown did not affect BDNF gene expression in resting or depolarized neurons. Accordingly, the positive correlation between Nurr1 and BDNF expression in AQ and membrane depolarization experiments does not imply co-regulation because Nurr1 knockdown did not affect BDNF gene expression in resting or depolarized cortical neurons. Therefore, in contrast to midbrain dopaminergic neurons and cerebellar granule cells, Nurr1 does not regulate BDNF in cortical neurons. Full article

(This article belongs to the Special Issue Molecules Affecting Brain Development and Nervous System)

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Review

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18 pages, 1761 KiB

Open AccessReview

Role of SOCS and VHL Proteins in Neuronal Differentiation and Development

by Hiroshi Kanno, Shutaro Matsumoto, Tetsuya Yoshizumi, Kimihiro Nakahara, Atsuhiko Kubo, Hidetoshi Murata, Taro Shuin and Hoi-Sang U

Int. J. Mol. Sci. 2023, 24(4), 3880; https://doi.org/10.3390/ijms24043880 - 15 Feb 2023

Cited by 1 | Viewed by 2271

Abstract

The basic helix–loop–helix factors play a central role in neuronal differentiation and nervous system development, which involve the Notch and signal transducer and activator of transcription (STAT)/small mother against decapentaplegic signaling pathways. Neural stem cells differentiate into three nervous system lineages, and the [...] Read more.

The basic helix–loop–helix factors play a central role in neuronal differentiation and nervous system development, which involve the Notch and signal transducer and activator of transcription (STAT)/small mother against decapentaplegic signaling pathways. Neural stem cells differentiate into three nervous system lineages, and the suppressor of cytokine signaling (SOCS) and von Hippel-Lindau (VHL) proteins are involved in this neuronal differentiation. The SOCS and VHL proteins both contain homologous structures comprising the BC-box motif. SOCSs recruit Elongin C, Elongin B, Cullin5(Cul5), and Rbx2, whereas VHL recruits Elongin C, Elongin B, Cul2, and Rbx1. SOCSs form SBC-Cul5/E3 complexes, and VHL forms a VBC-Cul2/E3 complex. These complexes degrade the target protein and suppress its downstream transduction pathway by acting as E3 ligases via the ubiquitin–proteasome system. The Janus kinase (JAK) is the main target protein of the E3 ligase SBC-Cul5, whereas hypoxia-inducible factor is the primary target protein of the E3 ligase VBC-Cul2; nonetheless, VBC-Cul2 also targets the JAK. SOCSs not only act on the ubiquitin–proteasome system but also act directly on JAKs to suppress the Janus kinase–signal transduction and activator of transcription (JAK-STAT) pathway. Both SOCS and VHL are expressed in the nervous system, predominantly in brain neurons in the embryonic stage. Both SOCS and VHL induce neuronal differentiation. SOCS is involved in differentiation into neurons, whereas VHL is involved in differentiation into neurons and oligodendrocytes; both proteins promote neurite outgrowth. It has also been suggested that the inactivation of these proteins may lead to the development of nervous system malignancies and that these proteins may function as tumor suppressors. The mechanism of action of SOCS and VHL involved in neuronal differentiation and nervous system development is thought to be mediated through the inhibition of downstream signaling pathways, JAK-STAT, and hypoxia-inducible factor–vascular endothelial growth factor pathways. In addition, because SOCS and VHL promote nerve regeneration, they are expected to be applied in neuronal regenerative medicine for traumatic brain injury and stroke. Full article

(This article belongs to the Special Issue Molecules Affecting Brain Development and Nervous System)

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12 pages, 10708 KiB

Open AccessBrief Report

Downregulation of CDC25C in NPCs Disturbed Cortical Neurogenesis

by Xiaokun Zhou, Danping Lu, Wenxiang Yi and Dan Xu

Int. J. Mol. Sci. 2023, 24(2), 1505; https://doi.org/10.3390/ijms24021505 - 12 Jan 2023

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Abstract

Cell division regulators play a vital role in neural progenitor cell (NPC) proliferation and differentiation. Cell division cycle 25C (CDC25C) is a member of the CDC25 family of phosphatases which positively regulate cell division by activating cyclin-dependent protein kinases (CDKs). However, mice with [...] Read more.

Cell division regulators play a vital role in neural progenitor cell (NPC) proliferation and differentiation. Cell division cycle 25C (CDC25C) is a member of the CDC25 family of phosphatases which positively regulate cell division by activating cyclin-dependent protein kinases (CDKs). However, mice with the Cdc25c gene knocked out were shown to be viable and lacked the apparent phenotype due to genetic compensation by Cdc25a and/or Cdc25b. Here, we investigate the function of Cdc25c in developing rat brains by knocking down Cdc25c in NPCs using in utero electroporation. Our results indicate that Cdc25c plays an essential role in maintaining the proliferative state of NPCs during cortical development. The knockdown of Cdc25c causes early cell cycle exit and the premature differentiation of NPCs. Our study uncovers a novel role of CDC25C in NPC division and cell fate determination. In addition, our study presents a functional approach to studying the role of genes, which elicit genetic compensation with knockout, in cortical neurogenesis by knocking down in vivo. Full article

(This article belongs to the Special Issue Molecules Affecting Brain Development and Nervous System)

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