Sequential Role of SOXB2 Factors in GABAergic Neuron Specification of the Dorsal Midbrain

Makrides, Neoklis; Panayiotou, Elena; Fanis, Pavlos; Karaiskos, Christos; Lapathitis, George; Malas, Stavros

doi:10.3389/fnmol.2018.00152

Cited by 14 publications

(11 citation statements)

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“…GN11 cells were transduced with lentivirus and harvested 6 days later. Lentivirus was produced by transient transfection of 293T cells as described before (33, 34). The following clone was used from the TRC shRNA library: TRCN0000418150 (shMkrn3).…”

Section: Methodsmentioning

confidence: 99%

Central Precocious Puberty Caused by Novel Mutations in the Promoter and 5′-UTR Region of the Imprinted MKRN3 Gene

et al. 2019

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Background: Central Precocious Puberty (CPP) is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. To date, mutations in the coding region of KISS1, KISS1R, PROKR2, DLK1, and MKRN3 genes have been reported as causative for CPP. This study investigated the presence of causative mutations in both the promoter and the 5′-UTR regions of the MKRN3 gene.Methods: Sanger DNA sequencing was used for screening the proximal promoter and 5′-UTR region of the MKRN3 gene in a group of 73 index girls with CPP. Mutations identified were cloned in luciferase reporter gene vectors and transiently transfected in GN11 cells in order to check for changes in the activity of the MKRN3 promoter. GN11 cells were previously checked for Mkrn3 expression using lentivirus mediated knock-down. In silico analysis was implemented for the detection of changes in the mRNA secondary structure of the mutated MKRN3 5′-UTR.Results: Three novel heterozygous mutations (−166, −865, −886 nt upstream to the transcription start site) located in the proximal promoter region of the MKRN3 gene were identified in six non-related girls with CPP. Four of these girls shared the −865 mutation, one the −166, and another one the −886. A 5′-UTR (+13 nt downstream to the transcription start site) novel mutation was also identified in a girl with similar clinical phenotype. Gene reporter assay evaluated the identified promoter mutations and demonstrated a significant reduction of MKRN3 promoter activity in transfected GN11 cells. In silico analysis for the mutated 5′-UTR predicted a significant change of the mRNA secondary structure. The minimum free energy (MFE) of the mutated 5′-UTR was higher when compared to the corresponding wild-type indicating less stable RNA secondary structure.Conclusion: Our findings demonstrated novel genetic alterations in the promoter and 5′-UTR regulatory regions of the MKRN3 gene. These changes add to another region to check for the etiology of CPP.

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Section: Methodsmentioning

confidence: 99%

Central Precocious Puberty Caused by Novel Mutations in the Promoter and 5′-UTR Region of the Imprinted MKRN3 Gene

et al. 2019

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“…Interaction between SOX TFs and miRNAs involved in differentiation of astrocytes from NPCs is shown within red frame (Krichevsky et al, 2006;Zhou et al, 2018), while interaction between SOX TFs and miRNAs involved in differentiation of mature oligodendrocytes from oligodendrocytes progenitors is shown within orange frame (Dugas et al, 2010;Zhao et al, 2010;Gokey et al, 2012;Hoffmann et al, 2014;Reiprich et al, 2017;Nazari et al, 2018;Afrang et al, 2019;Wittstatt et al, 2020). Bylund et al, 2003;Graham et al, 2003;Scott et al, 2010;Hutton and Pevny, 2011 Promotion of neuronal differentiation SOX14, SOX21, SOX4, SOX11, SOX5, SOX6, SOX13 Connor et al, 1995;Hargrave et al, 2000;Sandberg et al, 2005;Wang et al, 2005;Bergsland et al, 2006;Kwan et al, 2008;Martinez-Morales et al, 2010;Chen et al, 2015;Makrides et al, 2018 Promotion of astrocytes differentiation SOX9 Stolt et al, 2003;Kang et al, 2012 Inhibition of astrocytes differentiation SOX3 Klum et al, 2018 Promotion of oligodendrocytes differentiation SOX8, SOX9, SOX10 Stolt et al, 2004;Stolt and Wegner, 2010;Weider et al, 2013 Inhibition of oligodendrocytes differentiation SOX5, SOX6 Stolt et al, 2006 miRNAs further repress Sox9 in oligodendroglial cells (Reiprich et al, 2017). This fine tuning of Sox9 and Sox10 expression levels leads to terminal differentiation of oligodendrocytes.…”

Section: Sox Transcription Factors and Micrornas In Control Of Neuronmentioning

confidence: 99%

“…Furthermore, the maintenance of Sox21 expression in NPCs disabled their terminal differentiation ( Sandberg et al, 2005 ). Interestingly, recent study shows that both SOX21 and SOX14 have their own unique gene targets and therefore these TFs do not compete for the same target genes ( Makrides et al, 2018 ). Thus, SOX21 is important for the maintenance, while SOX14 is necessary for terminal differentiation of the GABAergic neurons in the mouse brain ( Makrides et al, 2018 ).…”

Section: The Roles Of Sox Transcription Factors In Neuronal Differentmentioning

confidence: 99%

SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis

Stevanović

Drakulić

Lazic

et al. 2021

Front. Mol. Neurosci.

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The SOX proteins belong to the superfamily of transcription factors (TFs) that display properties of both classical TFs and architectural components of chromatin. Since the cloning of the Sox/SOX genes, remarkable progress has been made in illuminating their roles as key players in the regulation of multiple developmental and physiological processes. SOX TFs govern diverse cellular processes during development, such as maintaining the pluripotency of stem cells, cell proliferation, cell fate decisions/germ layer formation as well as terminal cell differentiation into tissues and organs. However, their roles are not limited to development since SOX proteins influence survival, regeneration, cell death and control homeostasis in adult tissues. This review summarized current knowledge of the roles of SOX proteins in control of central nervous system development. Some SOX TFs suspend neural progenitors in proliferative, stem-like state and prevent their differentiation. SOX proteins function as pioneer factors that occupy silenced target genes and keep them in a poised state for activation at subsequent stages of differentiation. At appropriate stage of development, SOX members that maintain stemness are down-regulated in cells that are competent to differentiate, while other SOX members take over their functions and govern the process of differentiation. Distinct SOX members determine down-stream processes of neuronal and glial differentiation. Thus, sequentially acting SOX TFs orchestrate neural lineage development defining neuronal and glial phenotypes. In line with their crucial roles in the nervous system development, deregulation of specific SOX proteins activities is associated with neurodevelopmental disorders (NDDs). The overview of the current knowledge about the link between SOX gene variants and NDDs is presented. We outline the roles of SOX TFs in adult neurogenesis and brain homeostasis and discuss whether impaired adult neurogenesis, detected in neurodegenerative diseases, could be associated with deregulation of SOX proteins activities. We present the current data regarding the interaction between SOX proteins and signaling pathways and microRNAs that play roles in nervous system development. Finally, future research directions that will improve the knowledge about distinct and various roles of SOX TFs in health and diseases are presented and discussed.

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“…K,L, The ratios of the pHH3-positive cells in the GFPpositive cells in the apical domain of the neural tube (K; taken from D 0 ,H 0 ,I 0 ) and IdU-positive cells in all GFP-positive cells (L; taken from Figures 3C and 5E 0 , J 0 ) were quantified Sox14 is required for terminal differentiation of dorsal midbrain GABAergic neurons. 39 In addition, Sox14 activates the p53 pathway to induce cell death in carcinoma cells. 18 While the context in which we analyzed the Sox14 function is different from these previous reports, the activities of Sox14 revealed from our analyses are consistent with these previous results; Sox14 is required for the promotion of neuronal differentiation.…”

Section: Sox14 Is Required For the Progression Of Neuronal Differentiationmentioning

confidence: 99%

Sox14 is essential for initiation of neuronal differentiation in the chick spinal cord

Katsuyama

Kadoya

Shirai

et al. 2021

Developmental Dynamics

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Background:The neural tube comprises several different types of progenitors and postmitotic neurons that co-ordinately act with each other to play integrated functions. Its development consists of two phases: proliferation of progenitor cells and differentiation into postmitotic neurons. How progenitor cells differentiate into each corresponding neuron is an important question for understanding the mechanisms of neuronal development.Results: Here we introduce one of the Sox transcription factors, Sox14, which plays an essential role in the promotion of neuronal differentiation. Sox14 belongs to the SoxB2 subclass and its expression starts in the progenitor regions before neuronal differentiation is initiated at the trunk level of the neural tube. After neuronal differentiation is initiated, Sox14 expression gradually becomes confined to the V2a region of the neural tube, where Chx10 is coexpressed. Overexpression of Sox14 restricts progenitor cell proliferation. Conversely, the blockade of Sox14 expression by the RNAi strategy inhibits V2a neuron differentiation and causes expansion of the progenitor domain. We further found that Sox14 acted as a transcriptional activator. Conclusions: Sox14 acts as a modulator of cell proliferation and is essential for initiation of neuronal differentiation in the chick neural tube.

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Sequential Role of SOXB2 Factors in GABAergic Neuron Specification of the Dorsal Midbrain

Cited by 14 publications

References 43 publications

Central Precocious Puberty Caused by Novel Mutations in the Promoter and 5′-UTR Region of the Imprinted MKRN3 Gene

Central Precocious Puberty Caused by Novel Mutations in the Promoter and 5′-UTR Region of the Imprinted MKRN3 Gene

SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis

Sox14 is essential for initiation of neuronal differentiation in the chick spinal cord

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