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PubMed2001

Fgf receptor signaling plays a role in lens induction.

We describe experiments showing that fibroblast growth factor receptor (Fgfr) signaling plays a role in lens induction. Three distinct experimental strategies were used: (1) using small-molecule inhibitors of Fgfr kinase activity, we showed that both the transcription level and protein expression of Pax6, a transcription factor critical for lens development, was diminished in the presumptive lens ectoderm; (2) transgenic mice (designated Tfr7) that expressed a dominant-negative Fgf receptor exclusively in the presumptive lens ectoderm showed defects in formation of the lens placode at E9.5 but in addition, showed reduced levels of expression for Pax6, Sox2 and Foxe3, all markers of lens induction; (3) by performing crosses between Tfr7 transgenic and Bmp7-null mice, we showed that there is a genetic interaction between Fgfr and Bmp7 signaling at the induction phases of lens development. This manifested as exacerbated lens development defects and lower levels of Pax6 and Foxe3 expression in Tfr7/Tfr7, Bmp7(+/-) mice when compared with Tfr7/Tfr7 mice alone. As Bmp7 is an established lens induction signal, this provides further evidence that Fgfr activity is important for lens induction. This analysis establishes a role for Fgfr signaling in lens induction and defines a genetic pathway in which Fgfr and Bmp7 signaling converge on Pax6 expression in the lens placode with the Foxe3 and Sox2 genes lying downstream.

Animals↗
PubMed2025

Generative model for the first cell fate bifurcation in mammalian development.

The first cell fate bifurcation in mammalian development directs cells toward either the trophectoderm (TE) or inner cell mass (ICM) compartments in pre-implantation embryos. This decision is regulated by the subcellular localization of a transcriptional co-activator YAP and takes place over several progressively asynchronous cleavage divisions. As a result of this asynchrony and variable arrangement of blastomeres, reconstructing the dynamics of the TE/ICM cell specification from fixed embryos is extremely challenging. To address this, we developed a live-imaging approach and applied it to measure pairwise dynamics of nuclear YAP and its direct target genes, CDX2 and SOX2, which are key transcription factors of the TE and ICM, respectively. Using these datasets, we constructed a generative model of the first cell fate bifurcation, which reveals the time-dependent statistics of the TE and ICM cell allocation. In addition to making testable predictions for the joint dynamics of the full YAP/CDX2/SOX2 motif, the model revealed the stochastic nature of the induction timing of the key cell fate determinants and identified the features of YAP dynamics that are necessary or sufficient for this induction. Notably, temporal heterogeneity was particularly prominent for SOX2 expression among ICM cells. As heterogeneities within the ICM have been linked to the initiation of the second cell fate decision in the embryo, understanding the origins of this variability is of key significance. The presented approach reveals the dynamics of the first cell fate choice and lays the groundwork for dissecting the next cell fate decisions in mouse development.

Animals↗
PubMed2004

Regulation of gene expression by Pax6 in ocular cells: a case of tissue-preferred expression of crystallins in lens.

Lens development is an excellent model for genetic and biochemical studies of embryonic induction, cell cycle regulation, cellular differentiation and signal transduction. Differentiation of lens is characterized by lens-preferred expression and accumulation of water-soluble proteins, crystallins. Crystallins are required for light transparency, refraction and maintenance of lens integrity. Here, we review mechanisms of lens-preferred expression of crystallin genes by employing synergism between developmentally regulated DNA-binding transcription factors: Pax6, c-Maf, MafA/L-Maf, MafB, NRL, Sox2, Sox1, RARbeta/RXRbeta, RORalpha, Prox1, Six3, gammaFBP-B and HSF2. These factors are differentially expressed in lens precursor cells, lens epithelium and primary and secondary lens fibers. They exert their function in combination with ubiquitously expressed factors (e.g. AP-1, CREB, pRb, TFIID and USF) and co-activators/chromatin remodeling proteins (e.g. ASC-2 and CBP/p300). A special function belongs to Pax6, a paired domain and homeodomain-containing protein, which is essential for lens formation. Pax6 is expressed in lens progenitor cells before the onset of crystallin expression and it serves as an important regulatory factor required for expression of c-Maf, MafA/L-Maf, Six3, Prox1 and retinoic acid signaling both in lens precursor cells and the developing lens. The roles of these factors are illustrated by promoter studies of mouse alphaA-, alphaB-, gammaF- and guinea pig zeta-crystallins. Pax6 forms functional complexes with a number of transcription factors including the retinoblastoma protein, pRb, MafA, Mitf and Sox2. We present novel data showing that pRb antagonizes Pax6-mediated activation of the alphaA-crystallin promoter likely by inhibiting binding of Pax6 to DNA.

Animals↗
PubMed2006

Analysis of Oct4-dependent transcriptional networks regulating self-renewal and pluripotency in human embryonic stem cells.

The POU domain transcription factor OCT4 is a key regulator of pluripotency in the early mammalian embryo and is highly expressed in the inner cell mass of the blastocyst. Consistent with its essential role in maintaining pluripotency, Oct4 expression is rapidly downregulated during formation of the trophoblast lineage. To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. Our data set includes regulators of ACTIVIN, BMP, fibroblast growth factor, and WNT signaling. These pathways are implicated in regulating human ESC differentiation and therefore further validate the results of our analysis. In addition, we identified a number of differentially expressed genes that are involved in epigenetics, chromatin remodeling, apoptosis, and metabolism that may point to underlying molecular mechanisms that regulate pluripotency and trophoblast differentiation in humans. Significant concordance between this data set and previous comparisons between inner cell mass and trophectoderm in human embryos indicates that the study of human ESC differentiation in vitro represents a useful model of early embryonic differentiation in humans.

Apoptosis↗
PubMed2005

Comparative genomics on mammalian Fgf3-Fgf4 locus.

The CCND1-ORAOV1-FGF19-FGF4-FGF3-TMEM16A-FADD-PPFIA1-CTTN (EMS1) locus at human chromosome 11q13.3 is amplified in head and neck tumors, esophageal cancer, Kaposi's sarcoma, bladder tumors, breast cancer, and liver cancer. Fgf4 mRNA is expressed in embryonic stem (ES) cells depending on Sox2 and Pou5f1 (Oct3/Oct4) transcription factors, and in myotomes and limb bud AER depending on MyoD (or Myf5) and GATA transcription factors. Here, rat Fgf3 and Fgf4 complete coding sequences were determined by using bioinformatics. Multiple errors, including one-base insertion and 22-base deletion, were identified within the coding region of rat Fgf4 RefSeq (NM_053809.1 or AB079673.1). Rat Fgf3 and Fgf4 genes, consisting of three exons, were clustered in tail-to-head manner with an interval of about 16 kb. CUTL1 (CCAAT-displacement protein, CDP) and NKX2-5 binding sites and TATA box within 5'-flanking promoter region were conserved among human, rat and mouse Fgf3 orthologs. MYOD and MYOG (Myogenin) binding sites and TATA box within 5'-flanking promoter region as well as GATA, MYOD, SOX2 and POU5F1 binding sites within exon 3 were conserved among mammalian Fgf4 orthologs. Human FGF3 and FGF4 genes were clustered in tail-to-head manner with an interval of about 35 kb. Major repetitive sequence (FGF34Rep1) and minor repetitive sequence (FGF34Rep2) were identified within human FGF3-FGF4 gene cluster. FGF34Rep1 were clustered within the FGF3-FGF4 locus as well as around the IL28RA locus (1p36.11) and the NFAM1 locus (22q13.2). FGF34Rep2 was characterized by the CCA(T/C) repeats. This is the first report on comparative genomics analyses on the Fgf3-Fgf4 locus within human, rat and mouse genomes.

Amino Acid Sequence↗
PubMed2025

A Protocol for Detecting DNA Methylation Changes at CpG Sites of Stemness-Related Genes in Aging Stem Cells.

Aging adversely affects the self-renewal and differentiation capabilities of stem cells, which impairs tissue regeneration as well as the homeostasis. Epigenetic mechanisms, specifically DNA methylation, play a key role in the maintenance of pluripotency in stem cells and regulation of pluripotency-related gene expression. Age-related modifications in methylation patterns could influence the expression of genes critical for stem cell potency maintenance, including transcription factors Nanog and Sox2. The following chapter describes a step-by-step bisulfite sequencing protocol for detection of methylation changes in the aging stem cells and provides valuable insights into the stem cells epigenetic profile. Further, the methodology describes the steps of genomic DNA extraction, bisulfite conversion, real-time PCR amplification, and sequencing for an in-depth view of the epigenetic profile derived from aging stem cells.

DNA Methylation↗
PubMed2005

A family with X-linked anophthalmia: exclusion of SOX3 as a candidate gene.

We report on a four-generation family with X-linked anophthalmia in four affected males and show that this family has LOD scores consistent with linkage to Xq27, the third family reported to be linked to the ANOP1 locus. We sequenced the SOX3 gene at Xq27 as a candidate gene for the X-linked anophthalmia based on the high homology of this gene to SOX2, a gene previously mutated in bilateral anophthlamia. However, no amino acid sequence alterations were identified in SOX3. We have improved the definition of the phenotype in males with anophthalmia linked to the ANOP1 locus, as microcephaly, ocular colobomas, and severe renal malformations have not been described in families linked to ANOP1.

Adult↗
PubMed2004

Comparative transcriptional profiling of two human embryonic stem cell lines.

Human embryonic stem cells (ESCs) have generated enormous interest due to their ability to self-renew and produce many different cell types. In conjunction with microarray technology, human ESCs provide a powerful tool for employing a systems-based approach to deciphering the molecular mechanisms that control pluripotency and early development. Recent work has focused on defining "stemness" and pluripotency based on different experimental and analytical approaches in both mouse and human ESCs. Using a mixed linear model statistical approach, we report a stringent direct comparison between data sets obtained from two human ESCs (BG01 and H1) in order to obtain a list of genes that are enriched in ESCs. In addition, we used another pluripotent population derived from BG01 ESCs to obtain a list of genes that we consider important to the maintenance of pluripotency. A total of 133 genes overlapped between the three pluripotent populations. A majority of the 133 genes were classified under the key functional categories of cell-cycle regulation, signaling, and regulation of transcription. Key genes expressed were Oct4, Sox2, LeftyA, and Fgf2. Also found to be enriched in all three populations is FLJ10713, a gene encoding a hypothetical protein of unknown function that has been shown in earlier studies to possess a homolog in mouse ESCs and also to cluster tightly with Oct4 in human ESCs. Although there were many genes unique to each pluripotent population, they shared similarities based on functional ontologies that define pluripotency. The significance of our studies underscores the need for direct comparison of stem cell populations that share biological similarities using uniform stringent analytical approaches, in order to better define pluripotency. Our findings have important implications for the maintenance of pluripotency and in developing directed differentiation strategies for various regenerative applications.

Algorithms↗
PubMed2006

Sox3 expression identifies neural progenitors in persistent neonatal and adult mouse forebrain germinative zones.

Neural precursors persist throughout life in the rodent forebrain subventricular zone (SVZ) and hippocampal dentate gyrus. The regulation of persistent neural stem cells is poorly understood, in part because of the lack of neural progenitor markers. The Sox B1 subfamily of HMG-box transcription factors (Sox1-3) is expressed by precursors in the embryonic nervous system, where these factors maintain neural progenitors in an undifferentiated state while suppressing neuronal differentiation. Sox2 expression persists in germinative zones of the adult rodent brain, but Sox3 expression in the postnatal brain remains largely unexplored. Here we examine Sox3 expression in the neonatal and adult mouse brain to gain insight into its potential involvement in regulating persistent neural stem cells and neurogenesis. We also investigate Sox3 expression during expansion and neural differentiation of postnatal mouse SVZ neural stem cell and human embryonic stem cell (hESC) cultures. We find that Sox3 is expressed transiently by proliferating and differentiating neural progenitors in the SVZ-olfactory bulb pathway and dentate gyrus. Sox3 immunoreactivity also persists in specific postmitotic neuronal populations. In vitro, high Sox3 protein expression levels in undifferentiated, SVZ-derived neurospheres decline markedly with differentiation. Sox3 immunoreactivity in hESCs appears upon differentiation to neural progenitors and then decreases as cells differentiate further into neurons. These findings suggest that Sox3 labels specific stages of hESC-derived and murine neonatal and adult neural progenitors and are consistent with a role for Sox3 in neural stem cell maintenance. Persistent Sox3 expression in some mature neuronal populations suggests additional undefined roles for Sox3 in neuronal function.

Animals↗
PubMed2006

Postnatal cellular contributions of the hippocampus subventricular zone to the dentate gyrus, corpus callosum, fimbria, and cerebral cortex.

The rodent dentate gyrus (DG) is formed in the embryo when progenitor cells migrate from the dentate neuroepithelium to establish a germinal zone in the hilus and a secondary germinal matrix, near the fimbria, called the hippocampal subventricular zone (HSVZ). The developmental plasticity of progenitors within the HSVZ is not well understood. To delineate the migratory routes and fates of progenitors within this zone, we injected a replication-incompetent retrovirus, encoding the enhanced green fluorescent protein (EGFP), into the HSVZ of postnatal day 5 (P5) mice. Between P6 and P45, retrovirally-infected EGFP(+) of progenitors migrated into the DG, established a reservoir of progenitor cells, and differentiated into neurons and glia. By P6-7, EGFP(+) cells were observed migrating into the DG. Subsets of these EGFP(+) cells expressed Sox2 and Musashi-1, characteristic of neural stem cells. By P10, EGFP(+) cells assumed positions within the DG and expressed immature neuronal markers. By P20, many EGFP(+) cells expressed the homeobox prospero-like protein Prox1, an early and specific granule cell marker in the CNS, and extended mossy fiber projections into the CA3. A subset of non-neuronal EGFP(+) cells in the dentate gyrus acquired the morphology of astrocytes. Another subset included EGFP(+)/RIP(+) oligodendrocytes that migrated into the fimbria, corpus callosum, and cerebral cortex. Retroviral injections on P15 labeled very few cells, suggesting depletion of HSVZ progenitors by this age. These findings suggest that the early postnatal HSVZ progenitors are multipotent and migratory, and contribute to both dentate gyrus neurogenesis as well as forebrain gliogenesis.

Animals↗
PubMed2006

Complementary expression pattern of Zfhx1 genes Sip1 and deltaEF1 in the mouse embryo and their genetic interaction revealed by compound mutants.

In mouse embryos, the Zfhx1 transcription factor genes, Sip1 and deltaEF1, are expressed in complementary domains in many tissues. Their possible synergism in embryogenesis was investigated by comparing the phenotype of Sip1-/-;deltaEF1-/- double homozygotes with single homozygous embryos. Unexpectedly, in Sip1-/- embryos deltaEF1 was ectopically activated, suggesting a negative regulation of deltaEF1 expression by Sip1. Sip1-/-;deltaEF1-/- embryos were similar to Sip1-/- embryos in short somite production and developmental arrest around E8.5, but showed more severe defects in dorsal neural tube morphogenesis accompanied by a larger reduction of Sox2 expression, ascribable to the loss of the ectopic deltaEF1 expression. Sip1+/-;deltaEF1-/- embryos develop various morphological defects after E10 that were absent in deltaEF1-/- embryos even in tissues without significant overlap of Sip1 and deltaEF1 expression, and arrested during mid gestation earlier than deltaEF1-/- embryos. These findings indicate that complex synergistic interactions occur between Zfhx1 transcription factor genes during mouse embryogenesis.

Animals↗
PubMed2006

Isolation and characterization of a novel gene, xMADML, involved in Xenopus laevis eye development.

We have identified Xenopus MADM-like (xMADML), a Xenopus laevis gene related to the murine MADM and the human NRBP genes. xMADML is expressed throughout early development and is expressed most strongly in the developing lens and more weakly in the retina and other anterior tissues. We demonstrate that disruption of xMADML translation by means of morpholino injection results in impaired retina and lens development. Reciprocal transplantation of the presumptive lens ectoderm between morpholino-injected embryos and those injected solely with a dextran lineage tracer demonstrates that xMADML is necessary in both the lens and the retina for correct development of these eye tissues. Analysis of gene expression after knockdown of xMADML revealed significant alterations in the expression of some genes, including Pax6, xSix3, Sox2, and Sox3, suggesting that xMADML plays a role in regulating gene expression during development of the eye. This investigation is the first in vivo study examining the developmental role of this novel gene and reveals an important role of xMADML in eye tissue development and differentiation.

Amino Acid Sequence↗
PubMed2006

Maternal expression and function of the Drosophila sox gene Dichaete during oogenesis.

Members of the Sox family of DNA-binding HMG domain proteins have been shown to regulate gene transcription in a wide range of developmental processes, including sex determination, neurogenesis, and chondrogenesis. However, little is known about their potential functions in developing germline tissues. In Drosophila, the Sox protein Dichaete (a.k.a., Fish-hook) is a member of the SoxB subgroup whose HMG domain shares strong sequence similarity to that of vertebrate Sox2. Dichaete exhibits dynamic expression in embryonic and larval stages and has pleiotropic functions in a variety of tissues. In this study, we extend analyses of Dichaete function and show that expression of Dichaete protein is detected in the developing oocyte during early to mid stages of oogenesis. Strikingly, Dichaete exhibits cytoplasmic distribution and is not detected in the oocyte nucleus. Germline mosaic analyses revealed that the Dichaete gene has maternal functions that influence dorsal/ventral patterning of the egg chamber. Dichaete mutant eggs exhibit defects in formation of the dorsal appendages, differentiation of dorsal/anterior follicle cells, and mislocalization of Gurken protein and gurken mRNA. Dichaete protein was shown to possess RNA-binding capabilities, suggesting a direct post-transcriptional role in regulating RNA functions.

Animals↗
PubMed2003

Maternal inheritance of Cre activity in a Sox2Cre deleter strain.

The Sox2 gene is expressed in several undifferentiated cell types. In an earlier study we described a Sox2Cre transgene that mediates epiblast-specific Cre-mediated modification of gene activity in the embryo. Here we report that this transgene is active in the female germline. Consequently, all offspring that arise from female mice heterozygous for the Sox2Cre transgene have demonstrable Cre activity irrespective of whether they inherit the transgene itself. Maternal inheritance of Cre activity allows the efficient modification of gene activity for functional analysis.

Alleles↗
PubMed2005

Normal lung development and function after Sox9 inactivation in the respiratory epithelium.

Heterozygous mutations in the human SOX9 gene cause campomelic dysplasia (CD), a skeletal malformation syndrome with various other organ defects. Severely affected CD patients usually die in the neonatal period due to respiratory distress. We analyzed the dynamic expression pattern of Sox9 in the developing mouse lung throughout morphogenesis. To determine a role of Sox9 in lung development and function, Sox9 was specifically inactivated in respiratory epithelial cells of the mouse lung using a doxycycline-inducible Cre/loxP system. Immunohistochemical and RNA analysis demonstrated extensive inactivation of Sox9 in the embryonic stage of lung development as early as embryonic day (E) 12.5. Lung morphogenesis and lung function after birth were not altered. Compensatory upregulation of Sox2, Sox4, Sox8, Sox10, Sox11, and Sox17 was not detected. Although Sox9 is expressed at high levels throughout lung morphogenesis, inactivation of Sox9 from the respiratory epithelial cells does not alter lung structure, postnatal survival, or repair following oxygen injury.

Animals↗
PubMed2007

Epigenetic modifiers promote efficient generation of neural-like cells from bone marrow-derived mesenchymal cells grown in neural environment.

Understanding mechanisms that govern cell fate decisions will lead to developing techniques for induction of adult stem cell differentiation to desired cell outcomes and, thus, production of an autologos source of cells for regenerative medicine. Recently, we demonstrated that stem cells derived from adult central nervous system or bone marrow grown with other cell lineages or with more undifferentiated cells sometimes take on those characteristics. This indicates that manipulating extracellular factors may be sufficient to alter some developmental restrictions regulated by the epigenetic system. In this study, using pharmacological agents that interfere with the main components of the epigenetic program such as DNA methylation and histone deacetylation, we induce high-level expression of embryonic and neural stem cell (NSC) marker Sox2 in bone marrow-derived mesenchymal stem cells (MSCs). Exposure of these modified cells to a neural environment via juxtacrine and paracrine interactions promote efficient generation of neural stem-like cells as well as cells with neuronal and glial characteristics. We concluded that the manipulation strategy used in this study can be a useful method for efficient production of NSC-like cells from MSCs.

Animals↗
PubMed2004

Isolation of retinal progenitor cells from post-mortem human tissue and comparison with autologous brain progenitors.

The goal of the present study was threefold: to determine whether viable human retinal progenitor cells (hRPCs) could be obtained from cadaveric retinal tissue, to evaluate marker expression by these cells, and to compare hRPCs to human brain progenitor cells (hBPCs). Retinas were dissected from post-mortem premature infants, enzymatically dissociated, and grown in the presence of epidermal growth factor and basic fibroblast growth factor. The cells grew as suspended spheres or adherent monolayers, depending on culture conditions. Expanded populations were banked or harvested for analysis by RT-PCR, immunocytochemistry, and flow cytometry. hBPCs derived from forebrain specimens from the same donors were grown and used for RT-PCR. Post-mortem human retinal specimens yielded viable cultures that grew to confluence repeatedly, although not beyond 3 months. Cultured hRPCs expressed a range of markers consistent with CNS progenitor cells, including nestin, vimentin, Sox2, Ki-67, GD2 ganglioside, and CD15 (Lewis X), as well as the tetraspanins CD9 and CD81, CD95 (Fas), and MHC class I antigens. No MHC class II expression was detected. hRPCs, but not hBPCs, expressed Dach1, Pax6, Six3, Six6, and recoverin. Minority subpopulations of hRPCs and hBPCs expressed doublecortin, beta-III tubulin, and glial fibrillary acidic protein, which is consistent with increased lineage restriction in subsets of cultured cells. Viable progenitor cells can be cultured from the post-mortem retina of premature infants and exhibit a gene expression profile consistent with immature neuroepithelial cells. hRPCs can be distinguished from hBPC cultures by the expression of retinal specification genes and recoverin.

Antigens, Differentiation↗
PubMed2026

Genomic Profiling of Anophthalmia/Microphthalmia-Associated CNVs Reveals Complex Genotype-Phenotype Correlations and Incomplete Penetrance.

BACKGROUND: Anophthalmia/microphthalmia (A/M) is a severe congenital ocular malformation characterized by the complete absence or small size of the eye bulb. Interpreting copy number variations (CNVs) in A/M is challenged by variable genotype-phenotype correlations and reduced penetrance. This study investigated the genetic etiology of A/M-associated CNVs. METHODS: Genomic profiling was performed on four unrelated families presenting with ocular anomalies or harboring A/M-susceptible CNVs. Variants were evaluated by integrating American College of Medical Genetics and Genomics (ACMG) guidelines with clinical phenotypes and familial segregation. RESULTS: An inherited 8.13 Mb deletion (8p23.3p23.1) in Patient 1 was excluded due to genotype-phenotype mismatch. Patients 2 and 3 harbored de novo pathogenic deletions involving OTX2 (14q22.3) and SOX2 (3q26.33), causing typical A/M. Case 4 revealed a 14q22.2q23.1 deletion encompassing OTX2 in a fetus and mother without ocular anomalies, consistent with the incomplete penetrance of OTX2-related microphthalmia. Thus, CNV-induced haploinsufficiency causes A/M with high phenotypic variability. CONCLUSION: Accurate CNV interpretation requires robust genotype-phenotype correlation and careful assessment of incomplete penetrance to prevent diagnostic pitfalls and improve genetic counseling.

Female↗