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

Receptor activator of nuclear factor (NF-kappaB) ligand (RANKL), its cellular receptor, receptor activator of NF-kappaB (RANK), and the decoy receptor osteoprotegerin (OPG) constitute a novel cytokine system. RANKL produced by osteoblastic lineage cells and activated T lymphocytes is the essential factor for osteoclast formation, fusion, activation, and survival, thus resulting in bone resorption and bone loss. RANKL activates its specific receptor, RANK located on osteoclasts and dendritic cells, and its signaling cascade involves stimulation of the c-jun, NF-kappaB, and serine/threonine kinase PKB/Akt pathways. The effects of RANKL are counteracted by OPG which acts as a soluble neutralizing receptor. RANKL and OPG are regulated by various hormones (glucocorticoids, vitamin D, estrogen), cytokines (tumor necrosis factor alpha, interleukins 1, 4, 6, 11, and 17), and various mesenchymal transcription factors (such as cbfa-1, peroxisome proliferator-activated receptor gamma, and Indian hedgehog). Transgenic and knock-out mice with excessive or defective production of RANKL, RANK, and OPG display the extremes of skeletal phenotypes, osteoporosis and osteopetrosis. Abnormalities of the RANKL/OPG system have been implicated in the pathogenesis of postmenopausal osteoporosis, rheumatoid arthritis, Paget's disease, periodontal disease, benign and malignant bone tumors, bone metastases, and hypercalcemia of malignancy, while administration of OPG has been demonstrated to prevent or mitigate these disorders in animal models. RANKL and OPG are also important regulators of vascular biology and calcification and of the development of a lactating mammary gland during pregnancy, indicating a crucial role for this system in extraskeletal calcium handling. The discovery and characterization of RANKL, RANK, and OPG and subsequent studies have changed the concepts of bone and calcium metabolism, have led to a detailed understanding of the pathogenesis of metabolic bone diseases, and may form the basis of innovative therapeutic strategies.
J Mol Med (Berl) 2001 Jun
PMID:Role of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in bone cell biology. 1148 16

European hedgehogs, Erinaceus europaeus and E. concolor, are among the many European plant and animal taxa that have been subjected to cyclical restriction to glacial refugia and interglacial expansion. An analysis of 95 mitotypes, comprising partial cytochrome b and control region sequences, shows deep divergence between the two hedgehog species. Three europaeus and two concolor clades are clearly identified and are consistent with previously identified refugia for Europe: the Iberian peninsula, Italy, and the Balkans. The degree of mitochondrial divergence among these clades suggests pre-Pleistocene separation of the refugial populations. In contrast, analysis of two nuclear introns clearly separates the two concolor clades, as in the mitochondrial data, but cannot discriminate the three europaeus clades. This discrepancy between nuclear and mitochondrial data is attributed to historical differences in the refugial population size of europaeus and concolor. The geographical distribution of mitotypes is analysed using nested clade analysis. This method, by including unobserved ('missing') mitotypes, can identify mitotype groupings that remain undetected in conventional analyses. However, the application of nested clade analysis to the study of refugial populations may be hampered by such factors as the loss of haplotypes from the refugial areas by repeated contractions of the population and the recent time scale of colonization relative to mutation rate.
Mol Ecol 2001 Sep
PMID:DNA footprints of European hedgehogs, Erinaceus europaeus and E. concolor: Pleistocene refugia, postglacial expansion and colonization routes. 1155 61

Oligodendrocyte precursor development in the embryonic spinal cord is thought to be regulated by the secreted signal, Sonic hedgehog (Shh). Such precursors can be identified by the expression of Olig genes, encoding basic helix-loop-helix factors, in the spinal cord and brain. However, the signaling pathways that govern oligodendrocyte precursor (OLP) development in the rostral central nervous system are poorly understood. Here, we show that Shh is required for oligodendrocyte development in the mouse forebrain and spinal cord, and that Shh proteins are both necessary and sufficient for OLP production in cortical neuroepithelial cultures. Moreover, adenovirus-mediated Olig1 ectopic expression can promote OLP formation independent of Shh activity. Our results demonstrate essential functions for Shh during early phases of oligodendrocyte development in the mammalian central nervous system. They further suggest that a key role of Shh signaling is activation of Olig genes.
Mol Cell Neurosci 2001 Oct
PMID:Sonic hedgehog is required during an early phase of oligodendrocyte development in mammalian brain. 1164 Aug 98

Neural tube defects (NTD) are clinically important congenital malformations whose molecular mechanisms are poorly understood. The loop-tail (Lp) mutant mouse provides a model for the most severe NTD, craniorachischisis, in which the brain and spinal cord remain open. During a positional cloning approach, we have identified a mutation in a novel gene, Lpp1, in the Lp mouse, providing a strong candidate for the genetic causation of craniorachischisis in LP: Lpp1 encodes a protein of 521 amino acids, with four transmembrane domains related to the Drosophila protein strabismus/van gogh (vang). The human orthologue, LPP1, shares 89% identity with the mouse gene at the nucleotide level and 99% identity at the amino acid level. Lpp1 is expressed in the ventral part of the developing neural tube, but is excluded from the floor plate where Sonic hedgehog (Shh) is expressed. Embryos lacking Shh express Lpp1 throughout the ventral neural tube, suggesting negative regulation of Lpp1 by SHH: Our findings suggest that the mutual interaction between Lpp1 and Shh may define the lateral boundary of floor plate differentiation. Loss of Lpp1 function disrupts neurulation by permitting more extensive floor plate induction by Shh, thereby inhibiting midline bending of the neural plate during initiation of neurulation.
Hum Mol Genet 2001 Oct 15
PMID:Severe neural tube defects in the loop-tail mouse result from mutation of Lpp1, a novel gene involved in floor plate specification. 1170 46

Kinematics and structural analyses were used as basic data to elaborate a dynamic quadruped model that may represent an unspecialized mammal. Hedgehogs were filmed on a treadmill with a cinefluorographic system providing trajectories of skeletal elements during locomotion. Body parameters such as limb segments mass and length, and segments centre of mass were checked from cadavers. These biological parameters were compiled in order to build a virtual quadruped robot. The robot locomotor behaviour was compared with the actual hedgehog to improve the model and to disclose the necessary changes. Apart from use in robotics, the resulting model may be useful to simulate the locomotion of extinct mammals.
Comp Biochem Physiol A Mol Integr Physiol 2001 Dec
PMID:Modelisation of an unspecialized quadruped walking mammal. 1173 72

In ventromedial cells of the developing CNS, Sonic hedgehog (Shh) has been shown to affect precursor proliferation, phenotype determination, and survival. Here we show that Shh and its receptor, Ptc-1, are expressed in the adult rat basal forebrain, and that Ptc-1 is expressed specifically by cholinergic neurons. In basal forebrain cultures, Shh was added alone and in combination with nerve growth factor (NGF), and the number of cholinergic neurons was determined by choline acetyltransferase (ChAT) immunocytochemistry. By 8 days in vitro, Shh and NGF show a synergistic effect: the number of ChAT-positive cells after treatment with both factors is increased over untreated cultures or cultures treated with either factor alone. While Shh increases the overall basal level of proliferation, double-labeling of dividing neuronal precursors with [(3)H]thymidine followed by ChAT immunocytochemistry after they mature, demonstrates that the specific increase in cholinergic neurons is not due to this proliferation enhancement. These experiments imply a role for Shh in the development of postmitotic cholinergic neurons and suggest a therapeutic value for Shh in neurodegenerative disease.
Mol Cell Neurosci 2002 Jan
PMID:Cooperative effects of Sonic Hedgehog and NGF on basal forebrain cholinergic neurons. 1181

The secreted protein hedgehog (Hh) plays a critical role in the developmental patterning of multiple tissues. In Drosophila melanogaster, a cytosolic multiprotein signaling complex appears necessary for Hh signaling. Genes that encode components of this Hh signaling complex (HSC) were originally identified and characterized based on their genetic interactions with hh, as well as with each other. It is only in recent years that the mechanistic functions of these components have begun to be unraveled. Here, we have investigated the relationship between two components of the HSC, the serine/threonine protein kinase Fused (Fu) and the kinesin-related protein Costal2 (Cos2). We have reconstituted a Fu/Cos2 complex in vitro and shown that Fu is able to directly associate with Cos2, forming a complex whose molecular size is similar to a previously described complex found in Drosophila cell extracts. We have also determined that the carboxyl-terminal domain of Fu is necessary and sufficient for the direct binding of Fu to Cos2. To validate the physiological relevance of this interaction, we overexpressed the carboxyl-terminal domain of Fu in wild-type flies. These flies exhibit a phenotype similar to that seen in fu mutants and consistent with an hh loss-of-function phenotype. We conclude that the carboxyl-terminal domain of Fu can function in a dominant negative manner, by preventing endogenous Fu from binding to Cos2. Thus, we provide the first evidence that Hh signaling can be compromised by targeting the HSC for disruption.
Mol Cell Biol 2002 Mar
PMID:The carboxyl-terminal domain of the protein kinase fused can function as a dominant inhibitor of hedgehog signaling. 1183 21

Insights in molecular developmental biology in animals and humans are facilitating the understanding of pathophysiologic mechanisms in dysmorphogenesis or abnormalities in normal embryologic structural development. A milestone was recognition of the role of shh in morphogenesis of craniofacial structures, especially the development of holoprosencephaly. The dependence of hedgehog morphogens on cholesterol modification for normal hedgehog signaling function has particular relevance to disorders of cholesterol synthesis which manifest dysmorphogenesis. Four human disorders of morphogenesis (Smith-Lemli-Opitz syndrome, desmosterolosis, X-linked chondrodysplasia punctata, CHILD syndrome) have recently been shown to be caused by sterol abnormalities resulting from cholesterol biosynthesis enzyme deficiencies. This review summarizes the clinical, biochemical and molecular data in these disorders with an emphasis on understanding the pathophysiology of dysmorphogenesis.
Cell Mol Biol (Noisy-le-grand) 2002 Mar
PMID:Disorders of post-squalene cholesterol biosynthesis leading to human dysmorphogenesis. 1199 Apr 52

Progesterone (P4) plays a central role in normal uterine function, from embryo implantation in endometrium to establishment and maintenance of uterine quiescence during pregnancy in the myometrium. Considering its diverse physiological effects on female reproductive function, rather little is known about downstream events of P4 action. Recent progress in differential screening technologies facilitated identification of such inducible genes. We used uteri of wild-type and progesterone receptor null mutant mice as a starting material and screened for differentially expressed genes by medium-density cDNA expression array. Here, we report that the expression of the morphogen, Indian hedgehog (Ihh), is rapidly stimulated by P4 in the mouse uterus. The level of Ihh mRNA is induced within 3 h, after a single administration of P4 to ovariectomized mice. The induced Ihh mRNA and protein were localized to the luminal and glandular epithelial compartment of the endometrium. During pseudopregnancy, the Ihh mRNA level was transiently increased in the preimplantation period and d 3 and d 4 post coitum and then decreased rapidly at d 5 post coitum. Furthermore, the expression profile of patched-1, hedgehog interacting protein-1, and chicken ovalbumin upstream promoter-transcription factor II, genes known to be in the hedgehog signaling pathway in other tissues, followed the expression pattern of Ihh during the periimplantation period. Our results suggested that Ihh is regulated by P4, and the Ihh signaling axis may play a role in the preparation of the uterus for implantation during the periimplantation period.
Mol Endocrinol 2002 Oct
PMID:Identification of Indian hedgehog as a progesterone-responsive gene in the murine uterus. 1235 98

We have sequenced four new mitochondrial genomes to improve the stability of the tree for placental mammals; they are two insectivores (a gymnure, Echinosorex gymnurus and Formosan shrew Soriculus fumidus); a Formosan lesser horseshoe bat (Rhinolophus monoceros); and the New Zealand fur seal (Arctocephalus forsteri). A revision to the hedgehog sequence (Erinaceus europaeus) is also reported. All five are from the Laurasiatheria grouping of eutherian mammals. On this new data set there is a strong tendency for the hedgehog and its relative, the gymnure, to join with the other Laurasiatherian insectivores (mole and shrews). To quantify the stability of trees from this data we define, based on nuclear sequences, a major four-way split in Laurasiatherians. This ([Xenarthra, Afrotheria], [Laurasiatheria, Supraprimates]) split is also found from mitochondrial genomes using either protein-coding or RNA (rRNA and tRNA) data sets. The high similarity of the mitochondrial and nuclear-derived trees allows a quantitative estimate of the stability of trees from independent data sets, as detected from a triplet Markov analysis. There are significant changes in the mutational processes within placental mammals that are ignored by current tree programs. On the basis of our quantitative results, we expect the evolutionary tree for mammals to be resolved quickly, and this will allow other problems to be solved.
Mol Biol Evol 2002 Dec
PMID:Four new mitochondrial genomes and the increased stability of evolutionary trees of mammals from improved taxon sampling. 1244 98


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