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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid hormones are involved in the regulation of growth and metabolism in all vertebrates. Transthyretin is one of the extracellular proteins with high affinity for thyroid hormones which determine the partitioning of these hormones between extracellular compartments and intracellular lipids. During vertebrate evolution, both the tissue pattern of expression and the structure of the gene for transthyretin underwent characteristic changes. The purpose of this study was to characterize the position of Insectivora in the evolution of transthyretin in eutherians, a subclass of Mammalia. Transthyretin was identified by thyroxine binding and Western analysis in the blood of adult shrews, hedgehogs, and moles. Transthyretin is synthesized in the liver and secreted into the bloodstream, similar to the situation for other adult eutherians, birds, and diprotodont marsupials, but different from that for adult fish, amphibians, reptiles, monotremes, and Australian polyprotodont marsupials. For the characterization of the structure of the gene and the processing of mRNA for transthyretin, cDNA libraries were prepared from RNA from hedgehog and shrew livers, and full-length cDNA clones were isolated and sequenced. Sections of genomic DNA in the regions coding for the splice sites between exons 1 and 2 were synthesized by polymerase chain reaction and sequenced. The location of splicing was deduced from comparison of genomic with cDNA nucleotide sequences. Changes in the nucleotide sequence of the transthyretin gene during evolution are most pronounced in the region coding for the N-terminal region of the protein. Both the derived overall amino sequences and the N-terminal regions of the transthyretins in Insectivora were found to be very similar to those in other eutherians but differed from those found in marsupials, birds, reptiles, amphibians, and fish. Also, the pattern of transthyretin precursor mRNA splicing in Insectivora was more similar to that in other eutherians than to that in marsupials, reptiles, and birds. Thus, in contrast to the marsupials, with a different pattern of transthyretin gene expression in the evolutionarily "older" polyprotodonts compared with the evolutionarily "younger" diprotodonts, no separate lineages of transthyretin evolution could be identified in eutherians. We conclude that transthyretin gene expression in the liver of adult eutherians probably appeared before the branching of the lineages leading to modern eutherian species.
Mol Biol Evol 2000 Aug
PMID:The evolution of the thyroid hormone distributor protein transthyretin in the order insectivora, class mammalia. 1090 40

Adult hematopoietic differentiation is a developmental process that employs many of the same molecular mechanisms as embryogenesis. To explore the possibility that hedgehog signaling is involved in the control of hematopoietic differentiation, we screened a panel of human leukemia cell lines for the expression of Patched1 and Smoothened, the receptor and coreceptor for hedgehog ligands. Expression was found in multiple cell lines, and Patched1 expression was detected in normal marrow. Induction of myeloid differentiation in cell lines downregulated expression of both genes. When normal marrow mononuclear cells were grown in semisolid medium in the presence of 10 microM cyclopamine, development of colonies of granulocytic/monocytic lineage was unaffected in terms of both number and morphology. The number of erythroid colonies, however, was significantly reduced (P < 0.01). Furthermore, hemoglobinization was substantially delayed relative to controls in those erythroid colonies that did form. Incubation of hematopoietic progenitors with Shh-N and GM-CSF resulted in increased granulocyte/monocyte colonies (P < 0.01); the increase was blocked by cyclopamine. Incubation of hematopoietic progenitors with Shh-N and stem cell factor resulted in larger erythroid colonies. These results suggest that elements of the hedgehog signaling pathway are involved in the control of hematopoietic differentiation.
Blood Cells Mol Dis 2000 Aug
PMID:Erythroid differentiation in vitro is blocked by cyclopamine, an inhibitor of hedgehog signaling. 1104 37

Sonic hedgehog (Shh) signal transduction via the G-protein-coupled receptor, Smoothened, is required for proliferation of cerebellar granule neuron precursors (CGNPs) during development. Activating mutations in the Hedgehog pathway are also implicated in basal cell carcinoma and medulloblastoma, a tumor of the cerebellum in humans. However, Shh signaling interactions with cell cycle regulatory components in neural precursors are poorly understood, in part because appropriate immortalized cell lines are not available. We have utilized primary cultures from neonatal mouse cerebella in order to determine (i) whether Shh initiates or maintains cell cycle progression in CGNPs, (ii) if G(1) regulation by Shh resembles that of classical mitogens, and (iii) whether individual D-type cyclins are essential components of Shh proliferative signaling in CGNPs. Our results indicate that Shh can drive continued cycling in immature, proliferating CGNPs. Shh treatment resulted in sustained activity of the G(1) cyclin-Rb axis by regulating levels of cyclinD1, cyclinD2, and cyclinE mRNA transcripts and proteins. Analysis of CGNPs from cyclinD1(-/-) or cyclinD2(-/-) mice demonstrates that the Shh proliferative pathway does not require unique functions of cyclinD1 or cyclinD2 and that D-type cyclins overlap functionally in this regard. In contrast to many known mitogenic pathways, we show that Shh proliferative signaling is mitogen-activated protein kinase independent. Furthermore, protein synthesis is required for early effects on cyclin gene expression. Together, our results suggest that Shh proliferative signaling promotes synthesis of regulatory factor intermediates that upregulate or maintain cyclin gene expression and activity of the G(1) cyclin-Rb axis in proliferating granule neuron precursors.
Mol Cell Biol 2000 Dec
PMID:Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. 1107 3

Holoprosencephaly, or an undivided forebrain, is a complex brain malformation associated with Sonic hedgehog (Shh) mutations. Other causes of holoprosencephaly have converged upon the Shh signaling pathway: genetic and pharmacologic impairment of cholesterol synthesis, and the action of the steroidal alkaloid cyclopamine. This review focuses on recent studies aimed at determining how Shh signaling is affected by these causes of holoprosencephaly, whether they involve a common mechanism and the role played by cholesterol. Cholesterol is potentially important for both biogenesis of Shh and in signal transduction in Shh-responsive cells. Teratogens that induce holoprosencephaly appear to affect Shh signal transduction rather than Shh biogenesis. Analysis of these agents and other compounds that affect various aspects of cellular cholesterol distribution indicates that the role of cholesterol in Shh signal transduction is novel and complicated. The similarity of the Shh receptor, Patched (Ptc), to the Niemann-Pick Cl protein, which is involved in the vesicular trafficking of cholesterol, provides insight into the role of cholesterol and the action of compounds like cyclopamine.
Cell Mol Life Sci 2000 Nov
PMID:The role of cholesterol in Shh signaling and teratogen-induced holoprosencephaly. 1113 Jan 77

Missense mutations in fibroblast growth factor receptor 3 (FGFR3) result in several types of human skeletal dysplasia, including the neonatally lethal dwarfism known as thanatophoric dysplasia. An engineered Ser(365)-->Cys substitution in mouse FGFR3, which is equivalent to a mutation associated with thanatophoric dysplasia-I in humans, has now been shown to cause severe dwarfism but not neonatal death. The mutant mice exhibit shortened limbs as a result of markedly reduced proliferation and impaired differentiation of growth plate chondrocytes. The receptor-activating mutation also resulted in downregulation of expression of the Indian hedgehog (IHH) and parathyroid hormone-related protein (PTHrP) receptor genes, both of which are important for bone growth. Interactions between FGFR3- and PTHrP-receptor-mediated signals during endochondral ossification were examined with embryonic metatarsal bones maintained in culture under defined conditions. Consistent with the in vivo observations, FGF2 inhibited bone growth in culture and induced downregulation of IHH and PTHrP receptor gene expression. Furthermore, PTHrP partially reversed the inhibition of long bone growth caused by activation of FGFR3; however, it impaired the differentiation of chondrocytes in an FGFR3-independent manner. These observations suggest that FGFR3 and IHH-PTHrP signals are transmitted by two interacting parallel pathways that mediate both overlapping and distinct functions during endochondral ossification.
Hum Mol Genet 2001 Mar 01
PMID:A Ser(365)-->Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia. 1118 69

We have further characterized essential loci within the centric heterochromatin of the left arm of chromosome 3 (3L) of Drosophila melanogaster, using EMS, radiation and P element mutagenesis. We failed to find any new essential genes, a result that suggests a lower-than-average gene density in this region. Mutations affecting expression of the most proximal gene [lethal 1, l1 or l(3)80Fj] act as dominant suppressors of Polycomb (Pc), behavior which is consistent with a putative trithorax group (trx-G) gene. The third gene to the left of the centromere [lethal 3, l3 or l(3)80Fh] is likely to correspond to verthandi (vtd), a known trx-G gene that plays a role in the regulation of hedgehog (hh) expression and signalling. The intervening gene [lethal 2, l2 or l(3)80Fi] is required throughout development, and mutant alleles have interesting phenotypes; in various allelic combinations that survive, we observe fertility, bristle, wing, eye and cuticle defects.
Mol Gen Genet 2001 Feb
PMID:Essential genes in proximal 3L heterochromatin of Drosophila melanogaster. 1125 25

Developmental pathways first elucidated by genetic studies in the fruit fly, Drosophila melanogaster, are conserved in vertebrates, and disruption of these pathways has been associated with various human congenital anomalies. Many developmental genes continue to play an important role in regulation of cell growth and differentiation after embryogenesis, and mutations in some of these genes can result in cancer. Basal cell carcinoma (BCC) of the skin is the most common type of cancer in humans. Although most BCCs are sporadic, in rare cases, individuals have a hereditary disease, Gorlin syndrome, that predisposes to multiple skin tumors as well as a variety of birth defects. Mutations in the human homolog of a Drosophila gene, patched, underlie Gorlin syndrome. Genetic studies in Drosophila show that patched is part of the hedgehog signaling pathway, important in determining embryonic patterning and cell fate in multiple structures of the developing embryo. Human patched is mutated in sporadic as well as hereditary BCCs, and inactivation of this gene is probably a necessary if not sufficient step for tumor formation. Delineation of the biochemical pathway in which patched functions may lead to rational medical therapy for skin cancer and possibly other tumors.
Hum Mol Genet 2001 Apr
PMID:The hedgehog pathway and basal cell carcinomas. 1125 9

The implantation of the blastocyst into a nurturing endometrium involves two overlapping steps: 1. The blastocyst-endometrial luminal epithelial attachment. 2. The decidualization of the endometrial stroma. An intriguing question is how does the blastocyst identify the uterine implantation site. Current research is focused on hypothetical soluble signaling molecules released by the blastocyst for conditioning a discrete uterine luminal epithelial domain for implantation. A still unresolved issue is the functional significance of receptor autophosphorylation following binding of uterine epithelial cell-derived heparin-binding epidermal growth factor-like growth factor to the epidermal growth factor receptor on trophoectodermic cell surfaces. With recent results hinting at the role of signaling proteins associated with the bone morphogenetic protein, fibroblast growth factor, WNT and hedgehog families to enable embryo implantation, the dynamics of uterine-embryo interaction becomes linked to fundamental cellular pathways of growth, differentiation and apoptosis.
Mol Reprod Dev 2001 Jun
PMID:Decidualization and implantation: embryo-uterine bioinformatics at work. 1138 50

Cell pattern in the ventral neural tube is organized by Sonic hedgehog (Shh) secreted by floor plate cells. To assay the range of direct Shh action, we developed a general method for blocking transduction of Hedgehog (Hh) signals through ectopic expression of a deleted form of the Hh receptor Patched (Ptc), termed Ptc(Deltaloop2). We validated this method in Drosophila and used mouse Ptc1(Deltaloop2) (mPtc1(Deltaloop2)) to block Shh transduction in the chick neural tube. mPtc1(Deltaloop2) expression caused cell-autonomous ventral-to-dorsal switches in progenitor identity and neuronal fate throughout the ventral neural tube, supporting a gradient mechanism whereby Shh acts directly and at long range. mPtc1(Deltaloop2) expression also caused the abnormal spread of Shh to more dorsal cells, indicating that Shh in the neural tube, like Hh in Drosophila, induces a feedback mechanism that limits its range of action.
Mol Cell 2001 Jun
PMID:A hedgehog-insensitive form of patched provides evidence for direct long-range morphogen activity of sonic hedgehog in the neural tube. 1143 Aug 30

The coordinated division of distinctive types of stem cells within an organ is crucial for organogenesis and homeostasis. Here we show genetic interactions among fs(1)Yb (Yb), piwi, and hedgehog (hh) that regulate the division of both germline stem cells (GSCs) and somatic stem cells (SSCs), the two constituent stem cell populations of the Drosophila ovary. Yb is required for both GSC and SSC divisions; loss of Yb function eliminates GSCs and reduces SSC division, while Yb overexpression increases GSC number and causes SSC overproliferation. We also show that Yb acts via the piwi- and hh-mediated signaling pathways that emanate from the same signaling cells to control GSC and SSC division, respectively. hh signaling also has a minor effect in GSC division.
Mol Cell 2001 Mar
PMID:Yb modulates the divisions of both germline and somatic stem cells through piwi- and hh-mediated mechanisms in the Drosophila ovary. 1146 75


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