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PubMed2004

Transcriptional regulation of mouse alphaB- and gammaF-crystallin genes in lens: opposite promoter-specific interactions between Pax6 and large Maf transcription factors.

Mammalian alphaB-crystallin is highly expressed both in lens epithelium and lens fibers. In contrast, gammaF-crystallin is highly expressed in the lens fiber cells. Crystallin gene expression in lens is regulated at the level of transcription by a sparse number of specific DNA-binding transcription factors. Here, we report studies on transcriptional regulation of mouse alphaB- and gammaF-crystallin promoters by specific combinations of Pax6/Pax6(5a), large Mafs (MafA, MafB, c-Maf, and NRL), Sox1, Sox2, Six3, and RARbeta/RXRbeta. Two sets of these factors, co-expressed both in lens epithelium and in lens fibers, were tested in co-transfection assays using cultured lens and non-lens cells. Regulation of alphaB-crystallin was studied in the presence of lens epithelial-factors Pax6, MafB, and RARbeta/RXRbeta, and lens fiber-factors Pax6, MafA, c-Maf, and NRL. Pax6 proteins activated the alphaB-crystallin promoter (-162 to +45) with any combination of Mafs. Addition of RARbeta/RXRbeta further increased its promoter activity. Gel shift assays using lens nuclear extracts demonstrated interactions of Pax6, Maf, and retinoic acid nuclear receptor proteins with two lens-specific regions, the distal LSR1 (-147/-118) and proximal LSR2 (-78/-40), of the alphaB-crystallin promoter. In contrast, Pax6 proteins acted as repressors of gammaF-crystallin promoter activity elicited by a combination of large Mafs, Sox, and RARbeta/RXRbeta proteins in transiently transfected lens and non-lens cells. The results show that Pax6 conversely regulates these two lens crystallin promoters. We propose that the opposite roles of Pax6 in crystallin gene regulation are results of different promoter architectures of the alphaB- and gammaF-crystallin genes, developmentally regulated association of transcription factors with the corresponding cis-regulatory sites, and specific recruitment of transcriptional co-activators and co-repressors by Pax6.

Animals↗
PubMed2004

SoxB transcription factors specify neuroectodermal lineage choice in ES cells.

Knowledge of lineage decision machinery in pluripotent embryonic stem (ES) cells may shed light on the process of germ layer segregation in the mammalian embryo and enable directed differentiation in vitro for biomedical applications. We have investigated the contribution of Class B1 Sox transcription factors to lineage choice during ES cell differentiation. We report that forced expression of Sox1 or Sox2 did not impair propagation of undifferentiated ES cells, but upon release from self-renewal promoted differentiation into neuroectoderm at the expense of mesoderm and endoderm. The efficient specification of a primary lineage by transcription factor manipulation provides a paradigm for instructing differentiation of ES cells for biopharmaceutical screening and cell therapy applications.

Animals↗
PubMed2004

FGF2 triggers iris-derived lens regeneration in newt eye.

Lens regeneration in newts occurs exclusively from the dorsal aspect of the iris pigment epithelium. Although the phenomenon has been a paradigm of experimental tissue regeneration, little is understood about how it is initiated and restricted to the dorsal iris. Here we show among various growth factors injected in an intact eye, a single injection of FGF2 specifically caused morphological changes of the iris characteristic of lens regeneration, induced expression of transcription factor genes Pax6, Sox2 and MafB, as well as endogenous Fgf2 in both dorsal and ventral halves, and provoked second lens development only from the dorsal iris. FGF2 protein accumulated in the iris tissue after the lens was removed, and injection of a soluble form of FGF receptor titrating FGF2 inhibited all reactions observed after the lens removal or after administration of FGF2. These results indicate that FGF2 and/or related molecules trigger lens regeneration from the dorsal iris in the newt. The observations also indicate that the absence of lens regeneration from the ventral iris is due to a block in a later phase of lens developmental pathway.

Animals↗
PubMed2005

Requirement of mesodermal retinoic acid generated by Raldh2 for posterior neural transformation.

Studies in amphibian embryos have suggested that retinoic acid (RA) may function as a signal that stimulates posterior differentiation of the nervous system as postulated by the activation-transformation model for anteroposterior patterning of the nervous system. We have tested this hypothesis in retinaldehyde dehydrogenase-2 (Raldh2) null mutant mice lacking RA synthesis in the somitic mesoderm. Raldh2(-/-) embryos exhibited neural induction (activation) as evidenced by expression of Sox1 and Sox2 along the neural plate, but differentiation of spinal cord neuroectodermal progenitor cells (posterior transformation) did not occur as demonstrated by a loss of Pax6 and Olig2 expression along the posterior neural plate. Spinal cord differentiation in Raldh2(-/-) embryos was rescued by maternal RA administration, and during the rescue RA was found to act directly in the neuroectoderm but not the somitic mesoderm. RA generated by Raldh2 in the somitic mesoderm was found to normally travel as a signal throughout the mesoderm and neuroectoderm of the trunk and into tailbud neuroectoderm, but not into tailbud mesoderm. Raldh2(-/-) embryos also exhibited increased Fgf8 expression in the tailbud, and decreased cell proliferation in tailbud neuroectoderm. Our findings demonstrate that RA synthesized in the somitic mesoderm is necessary for posterior neural transformation in the mouse and that Raldh2 provides the only source of RA for posterior development. An important concept to emerge from our studies is that the somitic mesodermal RA signal acts in the neuroectoderm but not mesoderm to generate a spinal cord fate.

Aldehyde Oxidoreductases↗
PubMed2005

Histone deacetylase 1 is essential for oligodendrocyte specification in the zebrafish CNS.

Histone deacetylases are critical components of transcriptional silencing mechanisms that regulate embryonic development. Recent work has shown that histone deacetylase 1 (hdac1) is required for neuronal specification during zebrafish CNS development. We show here that specification of oligodendrocytes, the myelinating cells of the CNS, also fails to occur in the hdac1 mutant hindbrain, but persistence of neural progenitors in the hindbrain ventricular zone, which express pax6a and sox2, is independent of hdac1 activity. Commitment of ventral neural progenitors to the oligodendrocyte fate is thought to require co-ordinate, hedgehog-dependent expression of olig2 and nkx2.2a in these cells, leading to expression of sox10 and subsequent differentiation of oligodendrocytes. Remarkably, transcription of olig2 is extinguished in ventral neural progenitors of the hdac1 mutant hindbrain, whereas expression of nkx2.2a is up-regulated in these cells, and sox10 expression is suppressed. Our results identify hdac1 as a novel, essential component of the mechanism that allocates neural progenitors to the oligodendrocyte fate, by attenuating expression of a subset of neural progenitor genes and rendering olig2 expression responsive to Hedgehog signalling.

Animals↗
PubMed2006

Epigenetic memory loss in aging oligodendrocytes in the corpus callosum.

In this study, we address the hypothesis that aging modifies the intrinsic properties of oligodendrocytes, the myelin-forming cells of the brain. According to our model, an "epigenetic memory" is stored in the chromatin of the oligodendrocyte lineage cells and is responsible for the maintenance of a mature phenotype, characterized by low levels of expression of transcriptional inhibitors. We report here an age-related decline of histone deacetylation and methylation, the molecular mechanisms responsible for the establishment and maintenance of this "epigenetic memory" of the differentiated state. We further show that lack of histone methylation and increased acetylation in mature oligodendrocytes are associated with global changes in gene expression, that include the re-expression of bHLH inhibitors (i.e. Hes5 and Id4) and precursor markers (i.e. Sox2). These changes characteristic of the "aging" oligodendrocytes can be recapitulated in vitro, by treating primary oligodendrocyte cultures with histone deacetylase inhibitors. Thus, we conclude that the "epigenetic memory loss" detected in white matter tracts of older mice induces global changes of gene expression that modify the intrinsic properties of aged oligodendrocytes and may functionally modulate the responsiveness of these cells to external stimuli.

Age Factors↗
PubMed2006

Transcription factor protein expression patterns by neural or neuronal progenitor cells of adult monkey subventricular zone.

The anterior subventricular zone of the adult mammalian brain contains progenitor cells which are upregulated after cerebral ischemia. We have previously reported that while a part of the progenitors residing in adult monkey anterior subventricular zone travels to the olfactory bulb, many of these cells sustain location in the anterior subventricular zone for months after injury, exhibiting a phenotype of either neural or neuronal precursors. Here we show that ischemia increased the numbers of anterior subventricular zone progenitor cells expressing developmentally regulated transcription factors including Pax6 (paired-box 6), Emx2 (empty spiracles-homeobox 2), Sox 1-3 (sex determining region Y-box 1-3), Ngn1 (neurogenin 1), Dlx1,5 (distalless-homeobox 1,5), Olig1,3 (oligodendrocyte lineage gene 1,3) and Nkx2.2 (Nk-box 2.2), as compared with control brains. Analysis of transcription factor protein expression by sustained neural or neuronal precursors in anterior subventricular zone revealed that these two cell types were positive for characteristic sets of transcription factors. The proteins Pax6, Emx2, Sox2,3 and Olig1 were predominantly localized to dividing neural precursors while the factors Sox1, Ngn1, Dlx1,5, Olig2 and Nkx2.2 were mainly expressed by neuronal precursors. Further, differences between monkeys and non-primate mammals emerged, related to expression patterns of Pax6, Olig2 and Dlx2. Our results suggest that a complex network of developmental signals might be involved in the specification of primate progenitor cells.

Analysis of Variance↗
PubMed2026

Generation of an induced pluripotent stem cell line, LGMi002-A, from a Bardet-Biedl Syndrome patient with a BBS5 homozygous pathogenic variant.

The human induced pluripotent stem cell (iPSC) line, iPSC-BBS5stbg1, derived from a patient with a Bardet-Biedl Syndrome (BBS) phenotype and carrying a BBS5 homozygous pathogenic variant: c.123delA, p.Gly42Glufs*11 is described. The reprogramming of the patient's dermal fibroblasts was achieved using the non-integrative Sendai virus system delivering the OCT4, SOX2, KLF4 and c-MYC (OSKM) transcription factors. The established iPSC line iPSC-BBS5stbg1 displays typical iPSC morphology, maintains genomic stability, and demonstrates the ability to differentiate into cell types representative of the three embryonic germ layers. This iPSC line constitutes robust and relevant cellular model for studying BBS-associated disease mechanisms and ciliary dysfunction.

Humans↗
PubMed2026

Generation of FCGR3A-EGFP knock-in reporter human embryonic stem cell line, WAe001-A-3S, using CRISPR/Cas9n-based gene targeting.

Fc gamma receptor IIIA (FCGR3A) encodes CD16a, a key mediator of antibody-dependent cellular cytotoxicity (ADCC) that regulates innate and adaptive immunity, especially in natural killer (NK) cells and monocytes. We generated an FCGR3A-EGFP knock-in human embryonic stem cell (hESC) line via CRISPR/Casn9n. The cell line showed a normal karyotype, maintained expression ofthe pluripotency markers OCT4, SOX2, and NANOG, and retained trilineage differentiation potential. This reporter line enables real-time tracking of FCGR3A expression during immune cell differentiation, serving as a useful tool for studying FCGR3A+ immune cell development and related immune mechanisms.

Humans↗
PubMed2005

From stem cells to neurons and glia: a Soxist's view of neural development.

During nervous system development, neural stem cells give rise to many different types of neurons and glia over an extended period. Little is known about the intrinsic factors that regulate stem-cell maintenance, decide whether neurons or glia are generated, or control terminal differentiation. Transcription factors of the Sox family provide important clues about the control of these events. In the central nervous system (CNS), Sox1, Sox2 and Sox3 are required for stem-cell maintenance, and their effects are counteracted by Sox21. Sox9, by contrast, alters the potential of stem cells from neurogenic to gliogenic, whereas Sox10 is essential for terminal oligodendrocyte differentiation. In the peripheral nervous system (PNS) the same Sox proteins have different functions, uncovering important developmental differences between the CNS and PNS.

Animals↗
PubMed2004

Molecular anatomy of placode development in Xenopus laevis.

We analyzed the spatiotemporal pattern of expression of 15 transcription factors (Six1, Six4, Eya1, Sox3, Sox2, Pax6, Pax3, Pax2, Pax8, Dlx3, Msx1, FoxI1c, Tbx2, Tbx3, Xiro1) during placode development in Xenopus laevis from neural plate to late tail bud stages. Out of all genes investigated, only the expression of Eya1, Six1, and Six4 is maintained in all types of placode (except the lens) throughout embryonic development, suggesting that they may promote generic placodal properties and that their crescent-shaped expression domain surrounding the neural plate defines a panplacodal primordium from which all types of placode originate. Double-labeling procedures were employed to reveal the precise position of this panplacodal primordium relative to neural plate, neural crest, and other placodal markers. Already at neural plate stages, the panplacodal primordium is subdivided into several subregions defined by particular combinations of transcription factors allowing us to identify the approximate regions of origin of various types of placode. Whereas some types of placode were already prefigured by molecularly distinct areas at neural plate stages, the epibranchial, otic, and lateral line placodes arise from a common posterior placodal area (characterized by Pax8 and Pax2 expression) and acquire differential molecular signatures only after neural tube closure. Our findings argue for a multistep mechanism of placode induction, support a combinatorial model of placode specification, and suggest that different placodes evolved from a common placodal primordium by successive recruitment of new inducers and target genes.

Animals↗
PubMed2004

Multiple roles for Nodal in the epiblast of the mouse embryo in the establishment of anterior-posterior patterning.

The TGFbeta family member Nodal has been shown to be involved in a variety of processes in development, including early axis formation. Here, we use a conditional gene inactivation strategy to show a specific requirement for Nodal in the epiblast. Complete inactivation of the Nodal locus in the epiblast using the Sox2-Cre deleter strain results in a failure to establish global anterior-posterior patterning, a phenotype that resembles the Nodal null phenotype. By contrast, mosaic inactivation of Nodal in the epiblast using the Mox2-Cre (MORE) deleter strain affects formation of the anterior mesendoderm and subsequent anterior neurectoderm patterning. Furthermore, ES cell chimera experiments indicate that Nodal-deficient ES cells preferentially populate the anterior compartment of the epiblast, suggesting that cell mixing in the epiblast is not random and that Nodal signaling mediates a novel anterior-posterior cell-sorting process within the epiblast before gastrulation.

Alleles↗
PubMed2005

Multiple N-cadherin enhancers identified by systematic functional screening indicate its Group B1 SOX-dependent regulation in neural and placodal development.

Neural plate and sensory placodes share the expression of N-cadherin and Group B1 Sox genes, represented by Sox2. A 219-kb region of the chicken genome centered by the N-cadherin gene was scanned for neural and placodal enhancers. Random subfragments of 4.5 kb average length were prepared and inserted into tkEGFP reporter vector to construct a library with threefold coverage of the region. Each clone was then transfected into N-cadherin-positive (lens, retina and forebrain) or -negative embryonic cells, or electroporated into early chicken embryos to examine enhancer activity. Enhancers 1-4 active in the CNS/placode derivatives and non-specific Enhancer 5 were identified by transfection, while electroporation of early embryos confirmed enhancers 2-4 as having activity in the early CNS and/or sensory placodes but with unique spatiotemporal specificities. Enhancers 2-4 are dependent on SOX-binding sites, and misexpression of Group B1 Sox genes in the head ectoderm caused ectopic development of placodes expressing N-cadherin, indicating the involvement of Group B1 Sox functions in N-cadherin regulation. Enhancers 1, 2 and 4 correspond to sequence blocks conserved between the chicken and mammalian genomes, but enhancers 3 and 5 are unique to the chicken.

Animals↗
PubMed2006

A role for the hypoblast (AVE) in the initiation of neural induction, independent of its ability to position the primitive streak.

The mouse anterior visceral endoderm (AVE) has been implicated in embryonic polarity: it helps to position the primitive streak and some have suggested that it might act as a "head organizer", inducing forebrain directly. Here we explore the role of the hypoblast (the chick equivalent of the AVE) in the early steps of neural induction and patterning. We report that the hypoblast can induce a set of very early markers that are later expressed in the nervous system and in the forebrain, but only transiently. Different combinations of signals are responsible for different aspects of this early transient induction: FGF initiates expression of Sox3 and ERNI, retinoic acid can induce Cyp26A1 and only a combination of low levels of FGF8 together with Wnt- and BMP-antagonists can induce Otx2. BMP- and Wnt-antagonists and retinoic acid, in different combinations, can maintain the otherwise transient induction of these markers. However, neither the hypoblast nor any of these factors or combinations thereof can induce the definitive neural marker Sox2 or the formation of a mature neural plate or a forebrain, suggesting that the hypoblast is not a head organizer and that other signals remain to be identified. Interestingly, FGF and retinoids, generally considered as caudalizing factors, are shown here to play a role in the induction of a transient "pre-neural/pre-forebrain" state.

Animals↗
PubMed2006

Generation of human cortical neurons from a new immortal fetal neural stem cell line.

Isolation and expansion of neural stem cells (NSCs) of human origin are crucial for successful development of cell therapy approaches in neurodegenerative diseases. Different epigenetic and genetic immortalization strategies have been established for long-term maintenance and expansion of these cells in vitro. Here we report the generation of a new, clonal NSC (hc-NSC) line, derived from human fetal cortical tissue, based on v-myc immortalization. Using immunocytochemistry, we show that these cells retain the characteristics of NSCs after more than 50 passages. Under proliferation conditions, when supplemented with epidermal and basic fibroblast growth factors, the hc-NSCs expressed neural stem/progenitor cell markers like nestin, vimentin and Sox2. When growth factors were withdrawn, proliferation and expression of v-myc and telomerase were dramatically reduced, and the hc-NSCs differentiated into glia and neurons (mostly glutamatergic and GABAergic, as well as tyrosine hydroxylase-positive, presumably dopaminergic neurons). RT-PCR analysis showed that the hc-NSCs retained expression of Pax6, Emx2 and Neurogenin2, which are genes associated with regionalization and cell commitment in cortical precursors during brain development. Our data indicate that this hc-NSC line could be useful for exploring the potential of human NSCs to replace dead or damaged cortical cells in animal models of acute and chronic neurodegenerative diseases. Taking advantage of its clonality and homogeneity, this cell line will also be a valuable experimental tool to study the regulatory role of intrinsic and extrinsic factors in human NSC biology.

Cell Differentiation↗
PubMed2003

Xenopus Nbx, a novel NK-1 related gene essential for neural crest formation.

The vertebrate neural crest is formed at the border between the neural plate and nonneural ectoderm during neurulation and eventually gives rise to a variety of cell types, including neurons, glia, facial chondrocytes and osteoblasts, and melanocytes. Although several secreted molecules, such as BMP, Wnts, FGF, and Noelin, have been implicated in neural crest formation, little is known about the precise intracellular mechanism underlying neural crest induction and differentiation. Here, we have identified a novel NK-1 class homeobox gene Nbx in Xenopus whose expression is correlated with neural crest formation. We also found that Nbx harbors an Eh1 domain and is a transcriptional repressor. Overexpression of Nbx suppressed neural plate makers and caused enhanced expression of the neural crest maker Slug. In contrast, the overexpression of a dominant negative form of Nbx during neurula stages suppressed the expression of the neural crest marker Slug and expanded neural markers such as Otx2 and Sox2. Taken together, we propose that Nbx is an essential transcriptional repressor required to permit neural crest induction by inhibiting the neural fate.

Animals↗
PubMed2000

Roles of Sox4 in central nervous system development.

The transcription factor-encoding gene, Sox4, is expressed in a wide range of tissues and has been shown to be functionally involved in heart, B-cell and reproductive system development. Sox4 shows a high degree of sequence homology with another group C Sox gene, Sox11, which is predominantly expressed in the CNS. Since the expression of Sox4 in the CNS has not been described we have carried out such a study. Sox4 and Sox11 expression increased simultaneously in the same early differentiating cells of the developing CNS except in the external granule layer of the cerebellum where Sox11 expression preceded that of Sox4. As development proceeded, their expression always appeared to relate to the maturational stage of the cell population, with Sox11 expression more transient than Sox4, except in the spinal cord where the reverse was true. Sox4 knock-out mice have been shown to die of a heart defect half way through gestation with no observable CNS phenotype. Our more detailed analysis showed no abnormality in the spatial restriction of expression of Sox2, Sox11, Mash1, neurogenin1 or neurogenin2, although the level of expression of Sox11 and Mash1 appeared a little different from the wild-type, implying that Sox4 might indeed have a functional role in CNS development. However, since Sox4 and Sox11 expression is so similar, we propose that Sox11 might compensate for the loss of Sox4 function in the CNS such that the phenotype is extremely mild in the Sox4 null mutant.

Aging↗
PubMed1998

Identification and functional analysis of the mouse lens filensin gene promoter.

Filensin (also called CP94; CP95; CP97; 115kDa protein) is a component of the lens-specific beaded filament which is believed to be functionally important in lens fiber cell differentiation and in maintaining lens fiber cell conformation and transparency. A 17.2kb fragment containing the 5'-upstream sequence of the filensin gene was isolated. S1-mapping analysis determined the transcription start point (tsp; +1) which locates at 94base pairs upstream from the initiating ATG on the filensin gene. In addition to a major tsp, a minor tsp (-136) was observed. DNA sequence of the fragment around the tsp (-2144 to +155) was identified. Analysis of the DNA sequence of the promoter region around tsp revealed two motifs with sequence homology to Sox2 and Maf recognition sequences in addition to one GATA-1 site, two Sp1 binding sites, and three AP-2 binding motifs. No TATA-box or CCAAT-motif was found around the tsp region. A series of sequentially deleted fragments of (-2144 to +40) were fused to firefly luciferase reporter plasmid pGL2 and tested for activity in chicken embryonic lens explants. A minimal promoter region for mouse filensin of (-70 to +40) was identified. The lens-specific promoter activity was detected using lens explants cultured within 12h after dissection. The activity was remarkably enhanced by culture in the presence of 5ng/ml of basic fibroblast growth factor. Each one of the Sp1 and AP-2 binding motifs was localized to the fragment of (-27 to +40) using electrophoretic mobility shift assays. These are the first data to identify the basic elements to the 5'-upstream sequences of the filensin gene, namely the tsp and the minimal filensin promoter.

Animals↗