共查询到20条相似文献,搜索用时 31 毫秒
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Ricardo C. Garcez Nicole M. Le Douarin Sophie E. Creuzet 《Cellular and molecular life sciences : CMLS》2014,71(11):2149-2164
The combinatorial expression of Hox genes is an evolutionarily ancient program underlying body axis patterning in all Bilateria. In the head, the neural crest (NC)––a vertebrate innovation that contributes to evolutionarily novel skeletal and neural features––develops as a structure free of Hox-gene expression. The activation of Hoxa2 in the Hox-free facial NC (FNC) leads to severe craniofacial and brain defects. Here, we show that this condition unveils the requirement of three Six genes, Six1, Six2, and Six4, for brain development and morphogenesis of the maxillo-mandibular and nasofrontal skeleton. Inactivation of each of these Six genes in FNC generates diverse brain defects, ranging from plexus agenesis to mild or severe holoprosencephaly, and entails facial hypoplasia or truncation of the craniofacial skeleton. The triple silencing of these genes reveals their complementary role in face and brain morphogenesis. Furthermore, we show that the perturbation of the intrinsic genetic FNC program, by either Hoxa2 expression or Six gene inactivation, affects Bmp signaling through the downregulation of Bmp antagonists in the FNC cells. When upregulated in the FNC, Bmp antagonists suppress the adverse skeletal and cerebral effects of Hoxa2 expression. These results demonstrate that the combinatorial expression of Six1, Six2, and Six4 is required for the molecular programs governing craniofacial and cerebral development. These genes are crucial for the signaling system of FNC origin, which regulates normal growth and patterning of the cephalic neuroepithelium. Our results strongly suggest that several congenital craniofacial and cerebral malformations could be attributed to Six genes’ misregulation. 相似文献
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Role of extracardiac factors in heart development 总被引:1,自引:0,他引:1
M L Kirby 《Experientia》1988,44(11-12):944-951
Many factors extrinsic to the developing heart play important roles in determining its final form. The neural crest has been shown to provide ectomesenchyme to the pharyngeal apparatus and outflow tract, as well as the postganglionic innervation of the heart. Ablation of the neural crest providing ectomesenchyme to the outflow tract results in various cardiac malformations. These malformations have in common either outflow and/or inflow tract malalignment. Although the reason for this malalignment is not understood, it is thought that hemodynamic parameters during early cardiac morphogenesis may be disrupted causing cardiac dysmorphogenesis. The most likely area for this alteration to occur is in the pharyngeal apparatus which houses the aortic arch arteries. Various possibilities are discussed. The innervation of the heart by neural crest-derived autonomic neurons and nodose placode-derived sensory neurons is outlined, and the interactions between the two progenitive sites is discussed. 相似文献
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Ghaskadbi S Patwardhan V Chakraborthy M Agrawal S Verma MK Chatterjee A Lenka N Parab PB 《Cellular and molecular life sciences : CMLS》2008,65(20):3312-3324
Cardiac myocytes are the first cells to differentiate during the development of a vertebrate embryo. A wide variety of molecules take part in various steps in this process. While exploring biologically active molecules from marine sources, we found that a constituent of perivitelline fluid from embryos of the Indian horseshoe crab can enhance growth and differentiation of chick embryonic heart. We have purified the factor and identified the cardiac promoting molecule to be a novel lectin. We show that this molecule influences cardiac development by increasing the number of cells constituting the heart and by modulating the expression of several cardiac development regulatory genes in chick embryos. Using mouse embryonic stem cells we show that the cardiac myocyte-enhancing capacity of this molecule extends to mammals and its effects can be blocked using methylated sugars. This molecule may prove to be an important tool in the study of cardiomyocyte differentiation. 相似文献
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Soscia SJ Tong M Xu XJ Cohen AC Chu J Wands JR de la Monte SM 《Cellular and molecular life sciences : CMLS》2006,63(17):2039-2056
In fetal alcohol syndrome (FAS), cerebellar hypoplasia is associated with impaired insulin-stimulated survival signaling.
This study characterizes ethanol dose-effects on cerebellar development, expression of genes required for insulin and insulin-like
growth factor (IGF) signaling, and the upstream mechanisms and downstream consequences of impaired signaling in relation to
acetylcholine (ACh) homeostasis. Pregnant Long Evans rats were fed isocaloric liquid diets containing 0%, 2%, 4.5%, 6.5%,
or 9.25% ethanol from gestation day 6. Ethanol caused dose-dependent increases in severity of cerebellar hypoplasia, neuronal
loss, proliferation of astrocytes and microglia, and DNA damage. Ethanol also reduced insulin, IGF-I, and IGF-II receptor
binding, insulin and IGF-I receptor tyrosine kinase activities, ATP, membrane cholesterol, and choline acetyltransferase (ChAT)
expression. In vitro studies linked membrane cholesterol depletion to impaired insulin receptor binding and insulin-stimulated ChAT. In conclusion,
cerebellar hypoplasia in FAS is mediated by insulin/IGF resistance with attendant impairments in energy production and ACh
homeostasis.
Received 4 May 2006; received after revision 13 June 2006; accepted 20 June 2006 相似文献
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Cerebral cavernous malformations (CCM) are neurovascular dysplasias that result in mulberry-shaped lesions predominantly located in brain and spinal tissues. Mutations in three genes are associated with CCM. These genes encode for the proteins KRIT1/CCM1 (krev interaction trapped 1/cerebral cavernous malformations 1), cerebral cavernous malformations 2, osmosensing scaffold for MEKK3 (CCM2/malcavernin/OSM), and cerebral cavernous malformations 3/programmed cell death 10 (CCM3/PDCD10). There have been many significant recent advances in our understanding of the structure and function of these proteins, as well as in their roles in cellular signaling. Here, we provide an update on the current knowledge of the structure of the CCM proteins and their functions within cellular signaling, particularly in cellular adhesion complexes and signaling cascades. We go on to discuss subcellular localization of the CCM proteins, the formation and regulation of the CCM complex signaling platform, and current progress towards targeted therapy for CCM disease. Recent structural studies have begun to shed new light on CCM protein function, and we focus here on how these studies have helped inform the current understanding of these roles and how they may aid future studies into both CCM-related biology and disease mechanisms. 相似文献
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Hearing molecules: contributions from genetic deafness 总被引:1,自引:0,他引:1
Considerable progress has been made over the past decade identifying many genes associated with deafness. With the identification
of these hereditary deafness genes and the proteins they encode, molecular elements of basic hearing mechanisms emerge. As
functional studies of these molecular elements become available, we can put together the pieces of the puzzle and begin to
reach an understanding of the molecular mechanisms of hearing. The goal of this review is to discuss studies over the past
decade that address the function of the proteins implicated in genetic deafness and to place them in the context of basic
molecular mechanisms in hearing. The first part of this review highlights structural and functional features of the cochlea
and auditory nerve. This background will provide a context for the second part, which addresses the molecular mechanisms underlying
cochlear function as elucidated by genetic causes of deafness.
Received 20 September 2006; received after revision 24 October 2006; accepted 5 December 2006 相似文献
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Identification of rate-limiting steps or components of intracellular second messenger systems holds promise to effectively
interfere with these pathways under pathological conditions. The emerging literature on a recently identified family of signalling
regulator proteins, called tribbles gives interesting clues for how these proteins seem to link several ‘independent’ signal
processing systems together. Via their unique way of action, tribbles co-ordinate the activation and suppression of the various
interacting signalling pathways and therefore appear to be key in determining cell fate while responding to environmental
challenges. This review summarises our current understanding of tribbles function and also provides an evolutionary perspective
on the various tribbles genes.
Received 10 January 2006; received after revision 20 March 2006; accepted 5 April 2006 相似文献
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Kallmann’s syndrome, a neuronal migration defect 总被引:1,自引:0,他引:1
Infertility and inability to smell are the phenotypical features of Kallmann’s syndrome (KS), a genetic disease which affects
1 in 10,000 males and 1 in 50,000 females, the majority of the cases being sporadic. The molecular pathogenesis of KS is complex
but mainly referable to the impairment of olfactory axon development and of the migration of gonadotropin-releasing hormone
(GnRH) neurons. Only two different genes have been identified so far as responsible for the disease: KAL1 and KAL2, encoding
anosmin-1 and fibroblast growth factor receptor 1 (FGFR1), respectively. In this review we focus our attention on insights
evoked by recent studies, which propose a new direct role for anosmin-1 in the migration GnRH neurons, and a fascinating hypothesis
of interactions between anosmin-1 and FGFR1 systems.
Received 23 December 2005; received after revision 31 May 2006; accepted 6 July 2006 相似文献
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The study of candidate genes over the past three decades has yielded notable successes in common-disease genetics. During
this time, however, interpretation of genetic association studies has been hampered by the use of clinical cohorts of inadequate
power and insufficient information on genetic variation in candidate genes. The unavailability of highthroughput and low-cost
genotyping technologies has also limited the scope of complex-disease genetic studies. More recently, however, the sequencing
and characterization of variation within the human genome has revolutionized genetic studies and enabled full genome-wide
scans for genes associated with disease. The identification of disease-associated (causative) genes has illuminated disease
mechanisms. The translation of this knowledge into direct clinical benefit in diagnosis, prognosis and therapy for an individual’s
disease still remains a challenge.
Received 11 September 2006; received after revision 17 December 2006; accepted 18 January 2007 相似文献
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L J Sweeney 《Experientia》1988,44(11-12):930-936
Cardiac development involves a complex integration of subcellular processes into multicellular and, finally, whole organ effects. Until recently it has been difficult to investigate the genetic control of this organ level differentiation of the heart. The proliferation of molecular biology methodologies has provided mechanisms to directly investigate the control of these processes. This article focuses on molecular lines of research on two key areas in cardiac development: the regulation of expression of sarcomeric contractile and regulatory proteins, and atrial natriuretic factor. Molecular approaches are described which have allowed investigators to begin to determine the tissue and stage-specific expression of genes, to locate those genes in the genome, determine their sequences, and to directly investigate the mechanisms controlling their expression. 相似文献
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Primary cilia are a class of cilia that are typically solitary, immotile appendages present on nearly every mammalian cell
type. Primary cilia are believed to perform specialized sensory and signaling functions that are important for normal development
and cellular homeostasis. Indeed, primary cilia dysfunction is now linked to numerous human diseases and genetic disorders.
Collectively, primary cilia disorders are termed as ciliopathies and present with a wide range of clinical features, including
cystic kidney disease, retinal degeneration, obesity, polydactyly, anosmia, intellectual disability, and brain malformations.
Although significant progress has been made in elucidating the functions of primary cilia on some cell types, the precise
functions of most primary cilia remain unknown. This is particularly true for primary cilia on neurons throughout the mammalian
brain. This review will introduce primary cilia and ciliary signaling pathways with a focus on neuronal cilia and their putative
functions and roles in human diseases. 相似文献
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Wendeler MW Jung R Himmelbauer H Gessner R 《Cellular and molecular life sciences : CMLS》2006,63(13):1564-1673
Cadherins are Ca2+-dependent transmembrane glycoproteins crucial for cell-cell adhesion in vertebrates and invertebrates. Classification of
this superfamily due to their phylogenetic relationship is currently restricted to three major subfamilies: classical, desmosomal
and protocadherins. Here we report evidence for a common phylogenetic origin of the kidney-specific Ksp- (Cdh16) and the intestine-specific LI-cadherin (Cdh17). Both genes consist of 18 exons and the positions of their exon-intron boundaries as well as their intron phases are perfectly
conserved. We found an extensive paralogy of more than 40 megabases in mammals as well as teleost fish species encompassing
the Ksp- and LI-cadherin genes. A comparable paralogy was not detected for other cadherin gene loci. These findings suggest
that the Ksp- and LI-cadherin genes originated by chromosomal duplication early during vertebrate evolution and support our
assumption that both proteins are paralogues within a separate cadherin family that we have termed 7D-cadherins.
Received 16 January 2006; received after revision 18 April 2006; accepted 11 May 2006 相似文献
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Comparative genome analyses reveal that most functional domains of human genes have homologs in widely divergent species.
These shared functional domains, however, are differentially shuffled among evolutionary lineages to produce an increasing
number of domain architectures. Combined with duplication and adaptive evolution, domain shuffling is responsible for the
great phenotypic complexity of higher eukaryotes. Although the domain-shuffling hypothesis is generally accepted, determining
the molecular mechanisms that lead to domain shuffling and novel gene creation has been challenging, as sequence features
accompanying the formation of known genes have been obscured by accumulated mutations. The growing availability of genome
sequences and EST databases allows us to study the characteristics of newly emerged genes. Here we review recent genome-wide
DNA and EST analyses, and discuss the three major molecular mechanisms of gene formation: (1) atypical spicing, both within
and between genes, followed by adaptation, (2) tandem and interspersed segmental duplications, and (3) retrotransposition
events.
Received 18 October 2006; received after revision 18 November 2006; accepted 28 November 2006 相似文献
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Deepak Atri Bruno Larrivée Anne Eichmann Michael Simons 《Cellular and molecular life sciences : CMLS》2014,71(5):867-883
Arteriovenous malformations occur when abnormalities of vascular patterning result in the flow of blood from arteries to veins without an intervening capillary bed. Recent work has revealed the importance of the Notch and TGF-β signaling pathways in vascular patterning. Specifically, Notch signaling has an increasingly apparent role in arterial specification and suppression of branching, whereas TGF-β is implicated in vascular smooth muscle development and remodeling under angiogenic stimuli. These physiologic roles, consequently, have implicated both pathways in the pathogenesis of arteriovenous malformation. In this review, we summarize the studies of endothelial signaling that contribute to arteriovenous malformation and the roles of genes implicated in their pathogenesis. We further discuss how endothelial signaling may contribute to vascular smooth muscle development and how knowledge of signaling pathways may provide us targets for medical therapy in these vascular lesions. 相似文献
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In human patients, blood coagulation disorders often associate with cancer, even in its early stages. Recently, in vitro and in vivo experimental models have shown that oncogene expression, or inactivation of tumour suppressor genes, upregulate genes that
control blood coagulation. These studies suggest that activation of blood clotting, leading to peritumoral fibrin deposition,
is instrumental in cancer development. Fibrin can indeed build up a provisional matrix, supporting the invasive growth of
neoplastic tissues and blood vessels. Interference with blood coagulation can thus be considered as part of a multifaceted
therapeutic approach to cancer.
Received 30 November 2005; received after revision 7 February 2005; accepted 8 February 2006 相似文献
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Matin A 《Cellular and molecular life sciences : CMLS》2007,64(11):1317-1322
The 129 mouse strain develops congenital testicular germ cell tumors (TGCTs) at a low frequency. TGCTs in mice resemble the
testicular tumors (teratomas) that occur in human infants. The genes that cause these tumors in 129 have not been identified.
The defect at the Ter locus increases TGCT incidence such that 94% of 129-Ter/Ter males develop TGCTs. The primary effect of the Ter mutation is progressive loss of primordial germ cells (PGCs) during embryonic development. This results in sterility in adult
Ter/Ter mice on all mouse strain backgrounds. However, on the 129 background, Ter causes tumor development in addition to sterility. Therefore, Ter acts as a modifier of 129-derived TGCT susceptibility genes. Ter was identified to be a mutation that inactivates the Dead-end1 (Dnd1) gene. In this perspective, I discuss the possible areas of future investigations to elucidate the mechanism of TGCT development
due to Dnd1 inactivation.
Received 29 September 2006; received after revision 29 January 2007; accepted 19 February 2007 相似文献