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Ion Channels in Human Pluripotent Stem Cells and Their Neural Derivatives
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Ritika Raghavan, Robert Juniewicz, Maharaib Syed, Michael Lin, Peng Jiang
With advances in cellular reprogramming research, the direct reprogramming approach aims to use transcription factors, small molecules, microRNAs, and epigenetic modifiers or a combination of them to convert somatic cells, such as skin fibroblasts, directly to functional neurons and glia (18–20). The original study that first reported the direct reprogramming of terminally differentiated mouse fibroblasts into induced neurons used three neuronal transcription factors: Brn2, Ascl1, and Myt1L, known as the “BAM” factors. The fibroblasts were observed to drastically change in morphology into and become neuronal cells without cell division through a transient stage (21). Along with the addition of NeuroD1, these BAM factors were also able to convert human fibroblasts to functional neurons (22). This method retains the advantages of the accelerated differentiation approach along with the added advantage of not having to use PSCs as the starting cells in culture as somatic cells are readily available (23).
Endocrinology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Mehul Dattani, Catherine Peters
MODY affects 1–2% of people with diabetes, and is inherited in an autosomal dominant manner. Six genes have been identified to date including HNF1A, Glucokinase, HNF1B (including renal cysts and diabetes), HNF4A, IPF1, and NEUROD1.
In vivo reprogramming
Published in Christine Hauskeller, Arne Manzeschke, Anja Pichl, The Matrix of Stem Cell Research, 2019
Neuronal loss is a common hallmark of many neurodegenerative diseases which can lead to functional impairments (Guo et al., 2014). Recently, the reprogramming of somatic cells to neurons has been introduced as a novel strategy in the enhancement of endogenous repair. The earliest report, by Vierbuchen et al., demonstrated that both embryonic and postnatal fibroblasts can be efficiently converted to neurons using the overexpression of neural lineage-specific transcription factors such as Ascl1, Brn2, and Myt1 (ABM). These induced neurons expressed a specific neuronal marker and had the ability for action potential firing (Vierbuchen et al., 2010). Further study by this group also showed that human fibroblasts converted to functional neurons by the introduction of ABM and NeuroD1 transcription factors into a culture medium (Pang et al., 2011). Interestingly, the Ascl1-induced neurons were mostly excitatory – revealing the generation of certain subtypes of neuron through this approach. In addition to the ectopic expression of transcription factors, neuronal induction can be achieved using certain microRNAs and small molecules (Chen et al., 2016). However, though the overexpression of neuronal-specific microRNAs such as miR-9/9* and miR-124 could convert human fibroblasts to neurons, the efficiency of this process was low and the overexpression of transcription factors was required to obtain functional neurons (Yoo et al., 2011). Delivery of transcription factors and microRNAs through viral injection has been noticed as the main problem for using this approach in patients (Li and Chen, 2016). An alternative method is the direct conversion of cells by the specific combinations of small molecules. Interestingly, Li et al. could convert 90% of fibroblasts to neurons using a combination of four small molecules (Li et al., 2015). Additionally, astrocytes have also been converted to neurons by a combination of small molecules (Zhang et al., 2015). Furthermore, induced neurons can be derived from the human fibroblasts of Alzheimer’s disease (AD) patients using small molecules (Hu et al., 2015). Despite the beneficial effects of chemical reprogramming, there is no possibility for the application of small molecules in vivo – and the induced cells have to be transplanted into an adult brain which still faces the hurdle of immunorejection (Li and Chen, 2016).
Role of glucocorticoid negative feedback in the regulation of HPA axis pulsatility
Published in Stress, 2018
Julia K Gjerstad, Stafford L Lightman, Francesca Spiga
Genomic mechanisms. CRH-induced activation of the cAMP/PKA pathway results in phosphorylation of CREB and subsequent transcription of POMC. In addition, CRH also activates the MAPK pathway (Kovalovsky et al., 2002) resulting in activation of the orphan nuclear receptor Nur77 (Philips et al., 1997). The binding of Nur77 to the NurRE within the POMC promoter is known to enhance pCREB-mediated gene transcription (Phillips et al., 1997). CORT mediates negative feedback by inhibiting ACTH synthesis through a mechanism that requires binding of activated GR to an nGRE within the POMC promoter (Drouin et al., 1989a, 1989b). In addition, GR can inhibit Nur77-induced POMC transcription through a protein–protein interaction mechanism (Martens et al., 2005; Philips et al., 1997). A recent study suggests an involvement of NeuroD1 in regulating POMC transcription (Parvin et al., 2017). In the absence of CORT, NeuroD1 interacts with the E-box on the POMC promoter and activates transcription (Poulin et al., 1997). Increased CORT concentration causes a repression of NeuroD1 expression, and hence less activation of POMC transcription (Parvin et al., 2017).
Targeting the Wnt/β-catenin pathway in neurodegenerative diseases: recent approaches and current challenges
Published in Expert Opinion on Drug Discovery, 2020
Annalucia Serafino, Daniela Giovannini, Simona Rossi, Mauro Cozzolino
Among the Wnt target genes, numerous are those related to neurogenesis as well as to neuron survival, maintenance, and plasticity in the adult brain. We briefly describe below some of those that are upregulated by the Wnt signaling cascade. The CCND1 gene encodes for the cyclin D1 protein, which regulates cell cycle progression and neuronal function, and promotes neuron differentiation and neurogenesis [59]. The NEUROD1 (neuronal differentiation 1) gene encodes for a proneural transcription factor essential for the development of the CNS, and particularly for the generation of granule cells in the hippocampus and cerebellum [60]. Other Wnt target genes that are up-regulated by Wnt signaling are those encoding for survivin, whose expression seems to be crucial for restoring neural progenitor cells (NPCs) proliferation by the neurogenic niche in the aged brain [61], and for Mmp9 (Matrix metalloproteinase 9), that affects embryonic and adult neurogenesis and neuron plasticity [62,63]. The β-catenin/LEF1 complex appears also to enhance the expression of CACNA1 G (calcium voltage-gated channel subunit alpha1 G) gene, that encodes for Cav3.1, the predominant T-type channel subunit present in mature thalamic neurons [64], and to directly regulate the promoter of NEUROGENIN 1, a gene implicated in cortical neuronal differentiation [65]. Moreover, β-catenin directly binds to the promoter region of NURR1 gene [66], which encodes the Nurr1 protein essential for both survival and final differentiation of ventral mesencephalic dopaminergic precursor neurons [67]. Finally, Wnt signaling seems to directly activate the BDNF gene, encoding for the brain-derived neurotrophic factor that plays important roles in neuronal survival, neurogenesis, differentiation, and neurite growth throughout the CNS [68].
Determinants and dynamics of pancreatic islet architecture
Published in Islets, 2022
One of the strongest determinants of islet architecture is β cell maturity. Between birth and weaning, rodent β cells undergo a maturation process that results in acquisition of the adult glucose stimulated insulin secretion response.95–97 To date, virtually all experiments in which mouse β cells were prevented from reaching their mature identity or were forced to lose it after it had been acquired showed some degree of concomitant loss of canonical core-mantle architecture, marked by intermingled α cells in the islet core. Preventing β cells from assuming mature identity during development by genetic deletion of the key transcription factors Pdx1, MafA, or NeuroD1 results in partial or complete loss of canonical mouse islet architecture.98–101 Similar results are seen in transgenic mice over-expressing the Nkx2.2-repressor domain in mature β-cells.102 This was also seen with over expression of a dominant-negative form of HNF-1α, which was associated with reduced expression of E-cadherin in the immature β cells.103 Likewise, when expression of the β cell progenitor transcription factor, HNF6a is forced past its normal temporal domain (after E18.5), β cells fail to mature and islets lose endocrine cell type sorting.104 The loss of endocrine cell type sorting following continued expression of HNF6a may be due to the subsequent decrease in expression of CTGF, as mice with CTGF deletion show intermixing of endocrine cell types in adult islets.105 Additionally, when mTOR is deleted in β cells before architecture develops, β cells fail to mature and islets remain elongated and close to the ducts.106 Other factors for which genetic disruption resulted in both loss of β cell maturation and loss of canonical islet architecture include DICR1 (when deleted in embryonic β cells),48 Synaptotagmin,107 αCatenin,108 and, to some extent, BMPR1α.109