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A Hemmati-Brivanlou

Publications and source records attributed to A Hemmati-Brivanlou.

At least 19 recordsLinked to original sources
PubMed2002

Cloning and developmental expression of Baf57 in Xenopus laevis.

Mammalian and Drosophila homologues of Baf57 have been previously isolated as being a subunit of SWI/SNF-like chromatin remodeling complexes. Here, we report the cloning and developmental expression of Xenopus Baf57. We isolated XBaf57 by using an expression cloning approach to identify novel modulators of Xenopus Smad7. XBaf57 co-operates with XSmad7 by increasing the expression of neural markers in ectodermal explants. XBaf57 is expressed in the ectoderm and pre-involuting mesoderm during gastrula stages and in the central nervous system during neurula and tailbud stages. These results raise the possibility that XBaf57 (or XBaf57-containing chromatin remodelling complexes) may be involved in the process of neural induction during Xenopus embryonic development.

Amino Acid Sequence↗
PubMed2001

Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase.

Smad proteins are key intracellular signaling effectors for the transforming growth factor-beta superfamily of peptide growth factors. Following receptor-induced activation, Smads move into the nucleus to activate transcription of a select set of target genes. The activity of Smad proteins must be tightly regulated to exert the biological effects of different ligands in a timely manner. Here, we report the identification of Smurf2, a new member of the Hect family of E3 ubiquitin ligases. Smurf2 selectively interacts with receptor-regulated Smads and preferentially targets Smad1 for ubiquitination and proteasome-mediated degradation. At higher expression levels, Smurf2 also decreases the protein levels of Smad2, but not Smad3. In Xenopus embryos, ectopic Smurf2 expression specifically inhibits Smad1 responses and thereby affects embryonic patterning by bone morphogenetic protein signals. These findings suggest that Smurf2 may regulate the competence of a cell to respond to transforming growth factor-beta/bone morphogenetic protein signaling through a distinct degradation pathway that is similar to, yet independent of, Smurf1.

Acetylcysteine↗
PubMed2000

OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways.

We have identified the 30-zinc finger protein OAZ as a DNA-binding factor that associates with Smads in response to BMP2, forming a complex that transcriptionally activates the homeobox regulator of Xenopus mesoderm and neural development, Xvent-2. OAZ contains a BMP signaling module formed by two clusters of fingers that bind Smads and the Xvent-2 BMP response element, respectively. Previously implicated as a transcriptional partner of Olf-1/EBF in olfactory epithelium and lymphocyte development in the rat, OAZ fulfills this role through clusters of fingers that are separate from the BMP signaling module. The mutually exclusive use of OAZ by the BMP-Smad and Olf pathways illustrates the dual role of a multi-zinc finger protein in signal transduction during development.

Amino Acid Sequence↗
PubMed2000

A post-mid-blastula transition requirement for TGFbeta signaling in early endodermal specification.

In Xenopus, endodermal cell fate is determined gradually from late blastula to early gastrula stages; cell-cell interaction plays an important role in this process. Here we use a cell dissociation assay to show that extracellular signaling is required continuously before endoderm determination. Activin and Vg1, but not BMP2 or basic FGF, rescue the expression of endodermal markers in dissociated cells when provided at the mid-blastula transition (MBT, the time in which zygotic transcription begins). Removal of exogenously added activin or Vg1 before MBT results in reduction of endodermal gene expression in dissociated vegetal cells. In vivo, endogenous endodermal markers are reduced in vegetal explants when activin-like signaling is blocked with dominant negative receptors. VegT, a maternal transcription factor shown to be critical for endoderm specification, relies on an active TGFbeta pathway to induce endoderm in animal caps. These results indicate that TGFbeta signaling may be activated by the maternally expressed VegT to participate in endoderm determination. In addition, VegT function seems to be required in parallel with the TGFbeta pathway, as overexpression of activin does not relieve endoderm repression by a dominant negative VegT mutant in vegetal cells. Our data suggest that maternal VegT first activates a zygotic TGFbeta signal, then cooperates with this signal to determine the endodermal cell fate.

Activins↗
PubMed2000

Xenopus embryonic E2F is required for the formation of ventral and posterior cell fates during early embryogenesis.

Using an expression cloning approach, we have unveiled a novel function for the transcription factor E2F. We demonstrate that Xenopus E2F (xE2F) is required for patterning of the Xenopus embryonic axis. Overexpression of xE2F in embryos induces ectopic expression of ventral and posterior markers, including selected members of the Hox genes, and suppresses the development of dorsoanterior structures. Loss of xE2F function in embryos leads to the elimination of ventral and posterior structures. These observations suggest that xE2F acts as an important regulator of region-specific gene expression and in the formation of the embryonic axis. This study provides evidence for an additional embryonic function for E2F, independent of its well-documented role in cell cycle regulation, and suggests a novel mechanism of region-specific gene expression during vertebrate embryogenesis.

Amino Acid Sequence↗
PubMed1999

A molecular basis for Smad specificity.

Bone morphogenetic proteins (BMPs) and activins are members of the TGFbeta superfamily of growth factors, a crucial group of regulators of induction and patterning of embryonic germ layers in metazoa. In early Xenopus embryos, activin, Vgl, and nodal are potent inducers of dorsal mesoderm, whereas BMPs can ventralize mesoderm, repress neural fate, and induce blood differentiation. These characteristic responses rely on ligand-specific signaling pathways, encompassing transmembrane kinase receptors and signal transducers belonging to the Smad family. The overexpression in Xenopus embryos of BMP-activated Smad1 and of activin/Vg1/ nodal-activated Smad2 is sufficient to specifically recapitulate ligand responses. In a search for determinants of a Smad specificity code, we have identified two small regions within the conserved carboxyl-domain that are necessary and sufficient for specific Smad action. Swapping both residue clusters (C1 and C2) between Smadl and Smad2 completely switches Smad effects in vivo. Thus, Smadl with swapped Smad2 clusters responds specifically to BMP but elicits an activin response, while a Smad2 protein containing the Smadl clusters is activated by activin and elicits a BMP response. Furthermore, association between Smads and FAST-1, a mediator of mesoderm induction by activin, is dependent upon the presence of the Smad2 C1 sequence. Finally, the Smadl-specific antagonist Smad6 can inhibit a Smad2 molecule harboring Smadl C1 and C2 sequences. Thus, the C1 and C2 regions of Smads specify the association between Smads and pathway-specific partners, such as FAST-1 and Smad6, and account for activin- and BMP- specific responses in vertebrate embryogenesis.

Amino Acid Sequence↗
PubMed1999

Negative regulation of axis formation and Wnt signaling in Xenopus embryos by the F-box/WD40 protein beta TrCP.

Screening a maternal Xenopus expression library for activities that synergize with low levels of injected beta-catenin, we have isolated a clone encoding the C-terminal end of x-beta TrCP-2, a highly conserved protein belonging to the F-box/WD40 family of ubiquitin-ligase specificity factors. We show that x-beta TrCP-2 expression reduces dorsal axis formation in Xenopus embryos. A dominant negative mutant lacking the F-box triggers the opposite effect, inducing secondary axes and activating the expression of Wnt responsive genes in ectodermal explants. In light of the existence of beta TrCP transcripts associated with the vegetal cortex, we propose that beta TrCP plays a fundamental role in the establishment of the dorsal determinants during cortical rotation in Xenopus.

Animals↗
PubMed1999

Neural induction.

The formation of the vertebrate nervous system is initiated at gastrula stages of development, when signals from a specialized cluster of cells (the organizer) trigger neural development in the ectoderm. This process, termed neural induction, was first described in 1924 and stemmed from experiments on amphibia (Spemann & Mangold 1924). In recent years, the molecular mechanisms underlying neural induction in the amphibian have been elucidated. Surprisingly, neuralizing agents secreted by the organizer do not act via receptor-mediated signaling events; rather, these factors antagonize local epidermal inducers within the cells of the dorsal ectoderm and function to uncover the latent neural fate of these cells. Many of the recent advances in our understanding of vertebrate neural induction come from studies on the frog, Xenopus laevis. It is now clear that a blockade of signaling of the bone morphogenetic proteins (BMPs) during gastrula stages is sufficient to initiate neuralization of the ectoderm in this species. Thus this review first details our current understanding of neural induction, using the amphibian as a model. We then use data emerging from other systems to examine the extent to which the Xenopus studies can be applied to other vertebrate species. The initiation of the neurectoderm-specific gene expression program and subsequent steps in patterning and neuronal development are only touched on here. We focus primarily on the initial establishment of the neural fate in the vertebrate gastrula ectoderm.

Animals↗
PubMed1999

Xenopus GDF6, a new antagonist of noggin and a partner of BMPs.

In Xenopus, ectodermal cell fates are determined by antagonistic interaction between the BMP subfamily of TGF-(beta) ligands and the organizer-specific secreted factors (e.g. noggin, chordin and follistatin). Inhibition of BMP function by these factors can convert cells from an epidermal to a neural cell fate. In this study, we report that GDF6, a new member of the Xenopus TGF-(beta) family, can function in antagonistic interaction with neural inducers. GDF6 induces epidermis and inhibits neural tissue in dissociated cells, and this activity is blocked by the presence of noggin. We demonstrate that GDF6 binds directly to the neural inducer noggin. Furthermore, we find that GDF6 and BMP2 can form heterodimers and the process seems to require cotranslation of the proteins in the same cells. In normal embryos, GDF6 and BMP2 are coexpressed in several places, including the edge of the neural plate at early neurula stages, suggesting that GDF6 may synergize with BMPs to regulate patterning of the ectoderm. Our data show for the first time that noggin can bind directly to and inhibit another TGF-(beta) family member: GDF6. In addition, BMP and GDF6 heterodimers may play an important role in vivo to regulate cell fate determination and patterning.

Amino Acid Sequence↗
PubMed1999

Pax6 induces ectopic eyes in a vertebrate.

We report here that misexpression of the transcription factor Pax6 in the vertebrate Xenopus laevis leads to the formation of differentiated ectopic eyes. Multiple molecular markers indicated the presence of mature lens fiber cells, ganglion cells, Müller cells, photoreceptors and retinal pigment epithelial cells in a spatial arrangement similar to that of endogenous eyes. Lineage tracing experiments showed that lens, retina and retinal pigment epithelium arose as a consequence of the cell-autonomous function of Pax6. These experiments also reveal that the cell autonomous activity of misexpressed Pax6 causes the ectopic expression of a number of genes including Rx, Otx2, Six3 and endogenous Pax6, each of which has been implicated in eye development. The formation of ectopic and endogenous eyes could be suppressed by coexpression of a dominant-negative form of Pax6. These data show that in vertebrates, as in the invertebrate Drosophila melanogaster, Pax6 is both necessary and sufficient to trigger the cascade of events required for eye formation.

Animals↗
PubMed1998

FGF-mediated mesoderm induction involves the Src-family kinase Laloo.

During embryogenesis, inductive interactions underlie the development of much of the body plan. In Xenopus laevis, factors secreted from the vegetal pole induce mesoderm in the adjacent marginal zone; members of both the transforming growth factor-beta (TGF-beta) and fibroblast growth factor (FGF) ligand families seem to have critical roles in this process. Here we report the identification and characterization of laloo, a novel participant in the signal transduction cascade linking extracellular, mesoderm-inducing signals to the nucleus, where alteration of cell fate is driven by changes in gene expression. Overexpression of laloo, a member of the Src-related gene family, in Xenopus embryos gives rise to ectopic posterior structures that frequently contain axial tissue. Laloo induces mesoderm in Xenopus ectodermal explants; this induction is blocked by reagents that disrupt the FGF signalling pathway. Conversely, expression of a dominant-inhibitory Laloo mutant blocks mesoderm induction by FGF and causes severe posterior truncations in vivo. This work provides the first evidence that a Src-related kinase is involved in vertebrate mesoderm induction.

Amino Acid Sequence↗
PubMed1998

Neural crest induction by Xwnt7B in Xenopus.

Neural patterning occurs soon after neural induction during early development. In Xenopus, several caudalizing factors transform anterior neural to posterior neural tissue at the open neural plate stages, while other factors are responsible for setting up mediolateral polarity which becomes the dorsoventral (D-V) axis after neural tube closure. Many Wnt ligands are expressed in the neural tube in distinct anteroposterior (A-P) and D-V domains, implying a function in neural patterning. Here we report the cloning of a full-length Xenopus Wnt7B gene. Xwnt7B induces neural crest markers Xslug and Xtwist in ectodermal explants coinjected with neural inducer noggin and in ectodermal cells neuralized by dissociation. In vivo, Xwnt7B expands the Xtwist expression domain when injected in the animal pole. Our results suggest that Wnt members are involved in dorsoventral patterning of the neural tube.

Amino Acid Sequence↗
PubMed1998

Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor.

Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription. Here we report the existence of a natural inhibitor of this process, Smad6, a longer version of the previously reported JV15-1. In Xenopus embryos and in mammalian cells, Smad6 specifically blocks signaling by the BMP/Smad1 pathway. Smad6 inhibits BMP/Smad1 signaling without interfering with receptor-mediated phosphorylation of Smad1. Smad6 specifically competes with Smad4 for binding to receptor-activated Smad1, yielding an apparently inactive Smad1-Smad6 complex. Therefore, Smad6 selectively antagonizes BMP-activated Smad1 by acting as a Smad4 decoy.

Amino Acid Sequence↗
PubMed1998

A highly conserved lens transcriptional control element from the Pax-6 gene.

We have identified a short segment of the mouse Pax-6 gene 5' flanking region that is necessary and sufficient for reporter construct expression in components of the eye derived from non-neural ectoderm. This transcriptional control element has a highly conserved nucleotide sequence over 341 bp and is located approximately 3.5 kb upstream of the start-point for transcription from the most proximal promoter (PO) of the Pax-6 gene. The level of identity between the human and mouse Pax-6 genes in this region is 93%. When combined either with its natural promoter or a heterologous minimal promoter, this element directs reporter construct expression to a region of surface ectoderm overlying the optic cup beginning at E8.5-9.0 (12-14 somites). Subsequently, expression is restricted to the lens (primarily the lens epithelium) and the corneal epithelium. This element will provide an important tool in future transgenic analyses of lens formation and will allow identification of transcription factors with a central function in lens development.

Amino Acid Sequence↗
PubMed1998

Drosophila Goosecoid requires a conserved heptapeptide for repression of paired-class homeoprotein activators.

Goosecoid (Gsc) is a homeodomain protein expressed in the organizer region of vertebrate embryos. Its Drosophila homologue, D-Gsc, has been implicated in the formation of the Stomatogastric Nervous System. Although there are no apparent similarities between the phenotypes of mutations in the gsc gene in flies and mice, all known Gsc proteins can rescue dorsoanterior structures in ventralized Xenopus embryos. We describe how D-Gsc behaves as a transcriptional repressor in Drosophila cells, acting through specific palindromic HD binding sites (P3K). D-Gsc is a 'passive repressor' of activator homeoproteins binding to the same sites and an 'active repressor' of activators binding to distinct sites. In addition, D-Gsc is able to strongly repress transcription activated by Paired-class homeoproteins through P3K, via specific protein-protein interactions in what we define as 'interactive repression'. This form of repression requires the short conserved GEH/eh-1 domain, also present in the Engrailed repressor. Although the GEH/eh-1 domain is necessary for rescue of UV-ventralized Xenopus embryos, it is dispensable for ectopic induction of Xlim-1 expression, demonstrating that this domain is not required for all Gsc functions in vivo. Interactive repression may represent specific interactions among Prd-class homeoproteins, several of which act early during development of invertebrate and vertebrate embryos.

Amino Acid Sequence↗
PubMed1998

Cell fate determination in embryonic ectoderm.

During gastrulation in vertebrates the cells of the embryonic ectoderm give rise to epidermal progenitors in the ventral side and neural progenitors in the dorsal side. Despite many years of scrutiny, the molecular basis of these important embryonic cell fate decisions have not been solved. Only recently have we witnessed swift progress in the quest for factors involved in neural and epidermal induction. Several of what seem to be bona fide in vivo neural and epidermal inducers have been cloned, and the mechanism of their functions in embryos is also beginning to be understood. These new molecular results have revolutionized our view on the patterning of embryonic ectoderm and suggest that while the induction of epidermis requires instructive inductive signals, the establishment of neural fate occurs by default when epidermal inducers are inhibited. In this review, we discuss recent advances of our knowledge on epidermal and neural induction in the context of the "default model". We will then address the process of neurogenesis as well as recent findings on neural patterning. Emphasis is placed on, but not limited to, discoveries made in Xenopus, as most of our progress in understanding the ectodermal patterning is obtained from studies using this organism.

Animals↗
PubMed1997

Regulation of epidermal induction by BMP2 and BMP7 signaling.

The specification of neural fate in Xenopus embryos has been shown to be under regulation by negative factors. The secreted protein bone morphogenetic protein-4 (BMP4) has been identified as one of these factors: in the early gastrula ectoderm, BMP4 can both inhibit neural fate and induce epidermis. In this study, we show that two other Xenopus BMP genes, BMP2 and BMP7, are endowed with the same types of activities. First, we show that expression of a dominant negative form of the BMP2 ligand, which blocks normal processing of the wild-type ligand, causes neuralization of Xenopus ectoderm. Second, we have isolated the Xenopus BMP2/7 receptor (XALK2) and generated a constitutively active mutant that signals in a ligand-independent manner. We show that signals from the activated BMP2/7 receptor also inhibit neuralization and induce epidermis in dissociated ectoderm cells. Consistent with both findings we show that secreted BMP2 and BMP7 ligands can also mediate neural inhibition and epidermal induction. These results suggest that both BMP2 and BMP7 may be involved independently or together with BMP4 in the inhibition of the neural fate and the onset of the epidermal induction pathway in vivo. This further supports the idea that epidermal induction is due to the effects of multiple signals from heterogeneous BMP genes.

Animals↗