Showing papers by "University of California, San Francisco published in 1994"
TL;DR: Insight gained from studies of the signaling pathways downstream of TCR and BCR stimulation is likely to contribute significantly to future understanding of mechanisms responsible for lymphocyte differentiation and for the discrimination of self from nonself in developing and mature cells.
2,122 citations
TL;DR: Computer simulations were used to determine expected values of statistics that reflect frequency distributions of allele size for the two-phase model and two alternatives, the one-step and geometric models, and found that estimates of interpopulation distances from SSRs were similar to those derived from analysis of mitochondrial DNA.
Abstract: Mutational processes of simple sequence repeats (SSRs) in complex genomes are poorly understood. We examined these processes by introducing a two-phase mutation model. In this model, most mutations are single-step changes, but infrequent large jumps in repeat number also occur. We used computer simulations to determine expected values of statistics that reflect frequency distributions of allele size for the two-phase model and two alternatives, the one-step and geometric models. The theoretical expectations for each model were tested by comparison with observed values for 10 SSR loci genotyped in the Sardinian population, whose genetic and demographic histories have been previously reconstructed. The two-phase model provided the best fit to the data for most of these loci in this population. In the analysis we assumed that the loci were neutral and that this population had undergone rapid population growth. Recent observations made for unstable trinucleotide repeats support our suggestion that frequent small changes and rare large changes in repeat number represent two distinct classes of mutation at SSR loci. We genotyped the same 10 loci in Egyptian and sub-Saharan African samples to assess the utility of SSRs for studying the divergence of populations and found that estimates of interpopulation distances from SSRs were similar to those derived from analysis of mitochondrial DNA.
1,547 citations
1,480 citations
TL;DR: Direct evidence is presented that NMDA receptors exist in rat neocortex as heteromeric complexes of considerable heterogeneity, some containing both NR2A and NR2B subunits.
Abstract: ACTIVATION of the N-methyl-d-aspartate (NMDA) receptor is important for certain forms of activity-dependent synaptic plasticity, such as long-term potentiation (reviewed in ref. 1), and the patterning of connections during development of the visual system (reviewed in refs 2, 3). Several subunits of the NMDA receptor have been cloned: these are NMDAR1 (NR1), and NMDAR2A, 2B, 2C and 2D (NR2A-D)4–8. Based on heterologous co-expression studies, it is inferred that NR1 encodes an essential subunit of NMDA receptors and that functional diversity of NMDA receptors in vivo is effected by differential incorporation of subunits NR2A–NR2D5–8. Little is known, however, about the actual subunit composition or heterogeneity of NMDA receptors in the brain. By co-immunoprecipitation with subunit-specific antibodies, we present here direct evidence that NMDA receptors exist in rat neocortex as heteromeric complexes of considerable heterogeneity, some containing both NR2A and NR2B subunits. A progressive alteration in subunit composition seen postnatally could contribute to NMDA-receptor variation and changing synaptic plasticity during cortical development.
1,328 citations
TL;DR: It is shown that netrin-1 is a chemotropic factor expressed by floor plate cells and suggested that the two netrin proteins guide commissural axons in the developing spinal cord.
1,304 citations
TL;DR: A new form of synaptic plasticity, homosynaptic long-term depression (LTD) has also recently been documented, which, like LTP, requires Ca2+ entry through the NMDA receptor, and current work suggests that this LTD is a reversal ofLTP, and that the mechanisms of LTP and LTD may converge at the level of specific phosphoproteins.
1,300 citations
TL;DR: In this article, the authors have purified from embryonic chick brain two proteins, Netrin-1 and netrin-2, that each possess commissural axon outgrowth-promoting activity and also identified a distinct activity that potentiates their effects.
1,216 citations
TL;DR: It is demonstrated that Liddle's syndrome is caused by mutations in the beta subunit of the epithelial sodium channel and have implications for the regulation of this epithelial ion channel as well as blood pressure homeostasis.
1,174 citations
University of California, San Francisco1, University of Liège2, University of Oklahoma3, Columbia University4, Teikyo University5, Medical Research Council6, Scripps Research Institute7, University of Texas MD Anderson Cancer Center8, Harvard University9, Centre national de la recherche scientifique10, French Institute of Health and Medical Research11, Wayne State University12, University of Toronto13, Michigan State University14
1,098 citations
TL;DR: Recent optimized procedures for CGH are described, including DNA labeling, hybridization, fluorescence microscopy, digital image analysis, data interpretation, and quality control, emphasizing those steps that are most critical.
Abstract: Comparative genomic hybridization (CGH) is a powerful new method for molecular cytogenetic analysis of cancer. In a single hybridization, CGH provides an overview of DNA sequence copy number changes (losses, deletions, gains, amplifications) in a tumor specimen and maps these changes on normal chromosomes. CGH is based on the in situ hybridization of differentially labeled total genomic tumor DNA and normal reference DNA to normal human metaphase chromosomes. After hybridization and fluorescent staining of the bound DNAs, copy number variations among the different sequences in the tumor DNA are detected by measuring the tumor/normal fluorescence intensity ratio for each locus in the target metaphase chromosomes. CGH is in particular useful for analysis of DNA sequence copy number changes in common solid tumors where high-quality metaphase preparations are often difficult to make, and where complex karyotypes with numerous markers, double minutes, and homogeneously stained chromosomal regions are common. CGH only detects changes that are present in a substantial proportion of tumor cells (i.e., clonal aberrations). It does not reveal translocations, inversions, and other aberrations that do not change copy number. At present, CGH is a research tool that complements previous methods for genetic analysis. CGH will advance our understanding of the genetic progression of cancer and highlight important genomic regions for further study. Direct clinical applications of CGH are possible, but will require further development and validation of the technique. We describe here our recent optimized procedures for CGH, including DNA labeling, hybridization, fluorescence microscopy, digital image analysis, data interpretation, and quality control, emphasizing those steps that are most critical. We will also assess sensitivity and resolution limits of CGH as well as discuss possible future technical improvements. Genes Chromosom Cancer 10:231–243 (1994). © 1994 Wiley-Liss, Inc.
1,074 citations
TL;DR: A signalling pathway in which calcineurin dephosphorylates and inactivates inhibitor-1 increases PP1 activity and contributes to the generation of LTD, which is suggested to be an activity-dependent decrease in synaptic efficacy.
Abstract: Long-term potentiation (LTP) is a synaptic mechanism thought to be involved in learning and memory Long-term depression (LTD), an activity-dependent decrease in synaptic efficacy, may be an equally important mechanism which permits neural networks to store information more effectively One form of LTD that has been observed in the hippocampus requires activation of postsynaptic NMDA (N-methyl-D-aspartate) receptors, a change in postsynaptic calcium concentration, and activation of postsynaptic serine/threonine protein phosphatase 1 (PP1) or 2A (PP2A) The mechanism by which PP1 or PP2A is regulated by synaptic activity is unclear because these protein phosphatases are not directly influenced by calcium concentration LTD induction may require activation of a more complex protein phosphatase cascade consisting of the Ca2+/calmodulin-dependent protein phosphatase, calcineurin, its phosphoprotein substrate, inhibitor-1, and PP1 We tested this hypothesis using calcineurin inhibitors as well as different forms of inhibitor-1 loaded into postsynaptic cells Our results suggest a signalling pathway in which calcineurin dephosphorylates and inactivates inhibitor-1 This in turn increases PP1 activity and contributes to the generation of LTD
TL;DR: The evidence from both literate and preliterate cultures is overwhelming in support of universals in facial expressions, and A.J. Russell's qualms about other aspects of the design of the studies of literate cultures have no merit.
Abstract: J. A. Russell (1994) misrepresents what universality means, misinterprets the evidence from past studies, and fails to consider or report findings that disagree with his position. New data are introduced that decisively answer the central question that Russell raises about the use of a forced-choice format in many of the past studies. This article also shows that his many other qualms about other aspects of the design of the studies of literate cultures have no merit. Russell's critique of the preliterate cultures is inaccurate; he does not fully disclose what those who studied preliterate subjects did or what they concluded that they had found. Taking account of all of Russell's qualms, my analysis shows that the evidence from both literate and preliterate cultures is overwhelming in support of universals in facial expressions.
TL;DR: The BDNF mutant homozygotes have substantially reduced numbers of cranial and spinal sensory neurons and expression of neuropeptide Y and calcium-binding proteins is altered in many neurons, suggesting they do not function normally.
TL;DR: It is shown that rat skeletal muscle expresses neuronal-type NO synthase and that activity varies among several respiratory and limb muscles, and that two physiological functions of NO in skeletal muscle are supported.
Abstract: REACTIVE oxygen intermediates modulate skeletal muscle contraction1,2, but little is known about the role of nitric oxide (NO). Here we show that rat skeletal muscle expresses neuronal-type NO synthase and that activity varies among several respiratory and limb muscles. Immunohistochemistry showed prominent staining of type II (fast) fibre cell membranes with antibodies against neuronal-type NO synthase. NO synthase activity in muscles correlated with type II fibre density. Resting diaphragm muscle produced detectable NOx, but no reactive oxygen intermediates. In contrast, actively contracting muscle generated increased levels of reactive oxygen intermediates. Contractile function was augmented by blockers of NO synthase, extracellular NO chela-tion, and guanylyl cyclase inhibition; it was depressed by NO donors and by increased levels of cyclic GMP. Force–frequency plots of different muscles showed an inverse correlation between NO synthase activity and force development. Our results support two physiological functions of NO in skeletal muscle. The first is to promote relaxation through the cGMP pathway3,4. The second is to modulate increases in contraction that are dependent on reactive oxygen intermediates and which are thought to occur through reactions with regulatory thiols on the sarcoplasmic reticulum5,6.
TL;DR: Cloned Drosophila homologs of rac and CDC42, Drac1, and Dcdc42 proteins cause qualitatively distinct morphological defects, suggesting that similar GTPases in the same subfamily have unique roles in morphogenesis.
Abstract: The small GTPases of the Rac/Rho/Cdc42 subfamily are implicated in actin cytoskeleton-membrane interaction in mammalian cells and budding yeast. The in vivo functions of these GTPases in multicellular organisms are not known. We have cloned Drosophila homologs of rac and CDC42, Dracl, and Dcdc42. They share 70% amino acid sequence identity with each other, and both are highly expressed in the nervous system and mesoderm during neuronal and muscle differentiation, respectively. We expressed putative constitutively active and dominant-negative Dracl proteins in these tissues. When expressed in neurons, Dracl mutant proteins cause axon outgrowth defects in peripheral neurons without affecting dendrites. When expressed in muscle precursors, they cause complete failure of, or abnormality in, myoblast fusion. Expressions of analogous mutant Dcdc42 proteins cause qualitatively distinct morphological defects, suggesting that similar GTPases in the same subfamily have unique roles in morphogenesis.
TL;DR: The pattern of defects suggest an essential role for LEF-1 in the formation of several organs and structures that require inductive tissue interactions in mice carrying a homozygous germ-line mutation in the LEf-1 gene.
Abstract: Lymphoid enhancer factor 1 (LEF-1) is a sequence-specific DNA-binding protein that is expressed in pre-B and T lymphocytes of adult mice, and in the neural crest, mesencephalon, tooth germs, whisker follicles, and other sites during embryogenesis. We have generated mice carrying a homozygous germ-line mutation in the LEF-1 gene that eliminates its protein expression and causes postnatal lethality. The mutant mice lack teeth, mammary glands, whiskers, and hair but show no obvious defects in lymphoid cell populations at birth. The LEF-1-deficient mice also lack the mesencephalic nucleus of the trigeminal nerve, the only neural crest-derived neuronal populations. Together, the pattern of these defects suggest an essential role for LEF-1 in the formation of several organs and structures that require inductive tissue interactions.
TL;DR: Patients randomly assigned to the high-dose regimen of adjuvant chemotherapy had significantly longer disease-free and overall survival if their tumors had c-erbB-2 overexpression, a useful marker to identify a subgroup of patients more likely than others to benefit from high doses of chemotherapy.
Abstract: Background The role of molecular markers in predicting the response to treatment of breast cancer is poorly defined. The Cancer and Leukemia Group B (CALGB) conducted a randomized adjuvant-chemotherapy trial (CALGB 8541) comparing three doses (high, moderate, and low) of cyclophosphamide, doxorubicin, and fluorouracil in 1572 women with node-positive breast cancer. This study (CALGB 8869) was designed to determine whether the DNA index, the S-phase fraction, c-erbB-2 expression, or p53 accumulation could be used as a marker to identify a subgroup of patients more likely than others to benefit from high doses of chemotherapy. Methods Tissue blocks were obtained from 442 patients randomly selected from the larger CALGB trial. Paraffin sections from the primary lesions were analyzed for DNA content, S-phase fraction, c-erbB-2 expression, and p53 accumulation. Results Patients randomly assigned to the high-dose regimen of adjuvant chemotherapy had significantly longer disease-free and overall survival if thei...
TL;DR: The P2x receptor provides a striking example of convergent evolution, whereby proteins have been fashioned with similar functional properties from subunits having very different structural characteristics.
Abstract: The adenosine-5'-triphosphate (ATP) molecule is an extracellular messenger in neural and non-neural tissues, where it activates several cell-surface-receptor subtypes, including G-protein-coupled receptors and ligand-gated ion channels. ATP-gated channels (termed P2x receptors) have been characterized on smooth muscle cells and autonomic and sensory neurons, where they mediate membrane depolarization and, in some cases, Ca2+ entry. P2x receptors are functionally heterogeneous, but resemble acetylcholine- and serotonin-gated channels with respect to ion selectivity and kinetic parameters of channel gating. We report here that despite such close functional similarities, the deduced sequence of a cloned P2x receptor predicts an unusual subunit structure resembling voltage-insensitive cation channels. Thus, the P2x receptor provides a striking example of convergent evolution, whereby proteins have been fashioned with similar functional properties from subunits having very different structural characteristics. There is sequence similarity between the ATP receptor and RP-2, a gene activated in thymocytes undergoing programmed cell death. RP-2 may encode a receptor for ATP or another metabolite released during apoptosis.
TL;DR: It is concluded that TGF-beta has the ability to modulate E-cadherin expression and induce a reversible epithelial to mesenchymal transdifferentiation in epithelial cells.
Abstract: The secreted polypeptide transforming growth factor-beta (TGF-beta) exerts its multiple activities through type I and II cell surface receptors. In epithelial cells, activation of the TGF-beta signal transduction pathways leads to inhibition of cell proliferation and an increase in extracellular matrix production. TGF-beta is widely expressed during development and its biological activity has been implicated in epithelial-mesenchymal interactions, e.g., in branching morphogenesis of the lung, kidney, and mammary gland, and in inductive events between mammary epithelium and stroma. In the present study, we investigated the effects of TGF-beta on mouse mammary epithelial cells in vitro. TGF-beta reversibly induced an alteration in the differentiation of normal mammary epithelial NMuMG cells from epithelial to fibroblastic phenotype. The change in cell morphology correlated with (a) decreased expression of the epithelial markers E-cadherin, ZO-1, and desmoplakin I and II; (b) increased expression of mesenchymal markers, such as fibronectin; and (c) a fibroblast-like reorganization of actin fibers. This phenotypic differentiation displays the hallmarks of an epithelial to mesenchymal transdifferentiation event. Since NMuMG cells make high levels of the type I TGF-beta receptor Tsk7L, yet lack expression of the ALK-5/R4 type I receptor which has been reported to mediate TGF-beta responsiveness, we evaluated the role of the Tsk7L receptor in TGF-beta-mediated transdifferentiation. We generated NMuMG cells that stably overexpress a truncated Tsk7L type I receptor that lacks most of the cytoplasmic kinase domain, thus function as a dominant negative mutant. These transfected cells no longer underwent epithelial to mesenchymal morphological change upon exposure to TGF-beta, yet still displayed some TGF-beta-mediated responses. We conclude that TGF-beta has the ability to modulate E-cadherin expression and induce a reversible epithelial to mesenchymal transdifferentiation in epithelial cells. Unlike other transdifferentiating growth factors, such as bFGF and HGF, these changes are accompanied by growth inhibition. Our results also implicate the Tsk7L type I receptor as mediating the TGF-beta-induced epithelial to mesenchymal transition.
TL;DR: The successful establishment of a postcrisis SV40 large T-antigen transformed epithelial cell line derived from human bronchial epithelium is described, and this cell line, 16HBE14o- cells, provides a valuable resource for studying the modulation of CFTR and its role in regulation of chloride ion transport in human airway epithelia as well as other aspects of human airways cell biology.
Abstract: A major limitation in the study of vectorial ion transport, secretion, and differentiated function in the human airway epithelium has been the lack of suitable cell culture systems. Progress in this direction has been made through the transformation of primary cultured epithelial cells. However, these transformants tend to lose differentiated properties with increasing serial passage, particularly following crisis. The suc cessful establishment of a postcrisis SV40 large T-antigen transformed epithelial cell line derived from human bronchial epithelium is described. This cell line, 16HBEI40-, retains differentiated epithelial mor phology and functions. Cell cultures show the presence of tight junctions and cilia, and monolayers gener ate transepithelial resistance, as measured in Ussing chambers, and retain iJ-adrenergic stimulation of cAMP-dependent chloride ion transport, measured either by ,6CI- efflux or as short-circuit current in Ussing chambers. The cells also increase chloride transport in response to bradykinin or calcium iono phore. In addition, 16HBE140-cells express levels of both the cystic fibrosis transmembrane conductance regulator (CFTR) mRNA and protein readily detectable by Northern and Western hybridization analysis, respectively. These cells provide a valuable resource for studying the modulation of CFTR and its role in regulation of chloride ion transport in human airway epithelium as well as other aspects of human airway cell biology. The human airway epithelium is pseudostratified, consisting of highly organized layers of polar cells with specific dif ferentiated functions. It includes ciliated columnar cells, basal cells, and secretory goblet cells that are linked by tight junctions. The tight junctions provide a barrier between the airway lumen and the underlying tissues and divide the epi thelial cells into apical and basolateral domains. Both of these plasma membrane compartments contain different populations of proteins that allow for directional flux of ions
TL;DR: A review and synthesis of the nursing literature (1986-1992) supports the claim of the centrality of transitions in nursing and three types of nursing therapeutics are discussed.
Abstract: Transition is a concept of interest to nurse researchers, clinicians, and theorists. This article builds on earlier theoretical work on transitions by providing evidence from the nursing literature. A review and synthesis of the nursing literature (1986-1992) supports the claim of the centrality of transitions in nursing. Universal properties of transitions are process, direction, and change in fundamental life patterns. At the individual and family levels, changes occurring in identities, roles, relationships, abilities, and patterns of behavior constitute transitions. At the organizational level, transitional change is that occurring in structure, function, or dynamics. Conditions that may influence the quality of the transition experience and the consequences of transitions are meanings, expectations, level of knowledge and skill, environment, level of planning, and emotional and physical well-being. Indicators of successful transitions are subjective well-being, role mastery, and the well-being of relationships. Three types of nursing therapeutics are discussed. A framework for further work is described.
TL;DR: The structure of the SRP and SRP Receptor is described in more detail in detail in the second part of this monograph.
Abstract: STRUCTURE OF THE SRP AND SRP RECEPTOR . NOlllelleiatllre . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SRP RNA SRP Structllre alld Assembly . SRP Proteill SlIbllllits . . . . . . .. . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SRP Receptor .
TL;DR: The data suggest that receptor-mediated binding or internalization of apoE-enriched beta-VLDL leads to isoform-specific differences in interactions with cellular proteins that affect neurite outgrowth.
Abstract: Apolipoprotein E4 (apoE4), one of the three common isoforms of apoE, has been implicated in Alzheimer's disease. The effects of apoE on neuronal growth were determined in cultures of dorsal root ganglion neurons. In the presence of beta-migrating very low density lipoproteins (beta-VLDL), apoE3 increased neurite outgrowth, whereas apoE4 decreased outgrowth. The effects of apoE3 or apoE4 in the presence of beta-VLDL were prevented by incubation with a monoclonal antibody to apoE or by reductive methylation of apoE, both of which block the ability of apoE to interact with lipoprotein receptors. The data suggest that receptor-mediated binding or internalization (or both) of apoE-enriched beta-VLDL leads to isoform-specific differences in interactions with cellular proteins that affect neurite outgrowth.
TL;DR: DNA bending induced by the H MG domain can facilitate the formation of higher-order nucleoprotein complexes, suggesting that HMG domain proteins may have an architectural role in assembling such complexes.
TL;DR: It is determined by immunocytochemistry that numb is a membrane-associated protein which localizes asymmetrically to one-half of the predivisional SOP cell, and functions to determine the fates of the secondary precursors.
TL;DR: Comparative genomic hybridization was applied to 5 breast cancer cell lines and 33 primary tumors to discover and map regions of the genome with increased DNA-sequence copy-number, indicating that these chromosomal regions may contain previously unknown genes whose increased expression contributes to breast cancer progression.
Abstract: Comparative genomic hybridization was applied to 5 breast cancer cell lines and 33 primary tumors to discover and map regions of the genome with increased DNA-sequence copy-number. Two-thirds of primary tumors and almost all cell lines showed increased DNA-sequence copy-number affecting a total of 26 chromosomal subregions. Most of these loci were distinct from those of currently known amplified genes in breast cancer, with sequences originating from 17q22-q24 and 20q13 showing the highest frequency of amplification. The results indicate that these chromosomal regions may contain previously unknown genes whose increased expression contributes to breast cancer progression. Chromosomal regions with increased copy-number often spanned tens of Mb, suggesting involvement of more than one gene in each region.
TL;DR: The preliminary neuropathologic criteria for progressive supranuclear palsy (PSP) are presented as proposed at a workshop held at the National Institutes of Health, Bethesda, MD, April 24 and 25, 1993.
Abstract: We present the preliminary neuropathologic criteria for progressive supranuclear palsy (PSP) as proposed at a workshop held at the National Institutes of Health, Bethesda, MD, April 24 and 25, 1993. The criteria distinguish typical, atypical, and combined PSP. A semiquantitative distribution of neurofibrillary tangles is the basis for the diagnosis of PSP. A high density of neurofibrillary tangles and neuropil threads in the basal ganglia and brain-stem is crucial for the diagnosis of typical PSP. Tau-positive astrocytes or their processes in areas of involvement help to confirm the diagnosis. Atypical cases of PSP are variants in which the severity or distribution of abnormalities deviates from the typical pattern. Criteria excluding the diagnosis of typical and atypical PSP are large or numerous infarcts, marked diffuse or focal atrophy, Lewy bodies, changes diagnostic of Alzheimer's disease, oligodendroglial argyrophilic inclusions, Pick bodies, diffuse spongiosis, and prion protein-positive amyloid plaques. The diagnosis of combined PSP is proposed when other neurologic disorders exist concomitantly with PSP.
TL;DR: In lupus-prone NZB/NZW filial generation mice, treatment with muCTLA4Ig blocked autoantibody production and prolonged life, even when treatment was delayed until the most advanced stage of clinical illness.
Abstract: The interaction of B7-related molecules on antigen-presenting cells with CD28 or CTLA-4 antigens on T cells provides a second signal for T cell activation. Selection inhibition of the B7-CD28 or B7-CTLA-4 interactions produces antigen-specific T cell unresponsiveness in vitro and suppresses immune function in vivo. To determine whether selective inhibition of the B7-CD28 or B7-CTLA-4 interactions could suppress spontaneous autoimmune disease, a B7-binding protein was generated by genetic fusion of the extracellular domain of murine CTLA-4 to the Fc portion of a mouse immunoglobulin G2a monoclonal antibody (muCTLA4Ig). In lupus-prone NZB/NZW filial generation (F1) mice, treatment with muCTLA4Ig blocked autoantibody production and prolonged life, even when treatment was delayed until the most advanced stage of clinical illness. These findings suggest a possible role for human CTLA4Ig in the treatment of autoimmune diseases in humans.
TL;DR: The T cell antigen receptor (TCR) initiates signals by interacting with cytoplasmic protein tyrosine kinases (PTKs) through a 17-residue sequence motif [called the antigen recognition activation motif (ARAM)] that is contained in the TCR zeta and CD3 chains.
Abstract: The T cell antigen receptor (TCR) initiates signals by interacting with cytoplasmic protein tyrosine kinases (PTKs) through a 17-residue sequence motif [called the antigen recognition activation motif (ARAM)] that is contained in the TCR zeta and CD3 chains. TCR stimulation induces the tyrosine phosphorylation of several cellular substrates, including the ARAMs. Lck kinase activity is required for phosphorylation of two conserved tyrosine residues in an ARAM. This phosphorylation leads to the recruitment of a second cytoplasmic PTK, ZAP-70, through both of the ZAP-70 Src homology 2 domains and its phosphorylation. Thus, TCR signal transduction is initiated by the sequential interaction of two PTKs with TCR ARAMs.
TL;DR: It is reported here that Fgf4 expression in the ridge can be regulated byshh-expressing cells, and Shh expression in mesenchyme can be activated by FGF4 in combination with retinoic acid, thus establishing a positive feedback loop between ZPA and ridge.
Abstract: Limb development depends on signals from the apical ectodermal ridge and underlying mesenchyme. Fibroblast growth factor (FGF) can replace the ridge and, because Fgf4 RNA is localized to the mouse posterior ridge, we proposed that FGF4 is the endogenous ridge signal. Ridge signals control limb outgrowth and maintain the zone of polarizing activity (ZPA) at the limb posterior margin, which is important in limb pattering: a ZPA graft to limb anterior mesenchyme causes cell respecification and mirror-image duplications. Sonic hedgehog (SHH) has polarizing activity, and Shh RNA co-localizes with ZPA activity, suggesting SHH is the endogenous polarizing signal. We have investigated the molecular regulation of Fgf4 and Shh expression. We report here that Fgf4 expression in the ridge can be regulated by Shh-expressing cells. Moreover, Shh expression in mesenchyme can be activated by FGF4 in combination with retinoic acid. Once induced, Shh expression can be maintained by FGF4 alone, thus establishing a positive feedback loop between ZPA and ridge.