Publications (10)40.7 Total impact
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Article: Zebrafish bcl2l is a survival factor in thyroid development.
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ABSTRACT: Regulated cell death, defined in morphological terms as apoptosis, is crucial for organ morphogenesis. While differentiation of the thyroid gland has been extensively studied, nothing is yet known about the survival mechanisms involved in the development of this endocrine gland. Using the zebrafish model system, we aim to understand whether genes belonging to the Bcl-2 family that control apoptosis are implicated in regulation of cell survival during thyroid development. Evidence of strong Bcl-2 gene expression in mouse thyroid precursors prompted us to investigate the functions played by its zebrafish homologs during thyroid development. We show that the bcl2-like (bcl2l) gene is expressed in the zebrafish thyroid primordium. Morpholino-mediated knockdown and mutant analyses revealed that bcl2l is crucial for thyroid cell survival and that this function is tightly modulated by the transcription factors pax2a, nk2.1a and hhex. Also, the bcl2l gene appears to control a caspase-3-dependent apoptotic mechanism during thyroid development. Thyroid precursor cells require an actively maintained survival mechanism to properly proceed through development. The bcl2l gene operates in the inhibition of cell death under direct regulation of a thyroid specific set of transcription factors. This is the first demonstration of an active mechanism to ensure survival of the thyroid primordium during morphogenesis.Developmental Biology 04/2012; 366(2):142-52. · 4.07 Impact Factor -
Article: Gene expression profiling at early organogenesis reveals both common and diverse mechanisms in foregut patterning.
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ABSTRACT: The thyroid and lungs originate as neighboring bud shaped outgrowths from the midline of the embryonic foregut. When and how organ specific programs regulate development into structures of distinct shapes, positions and functions is incompletely understood. To characterize, at least in part, the genetic basis of these events, we have employed laser capture microdissection and microarray analysis to define gene expression in the mouse thyroid and lung primordia at E10.5. By comparing the transcriptome of each bud to that of the whole embryo as well as to each other, we broadly describe the genes that are preferentially expressed in each developing organ as well as those with an enriched expression common to both. The results thus obtained provide a valuable resource for further analysis of genes previously unrecognized to participate in thyroid and lung morphogenesis and to discover organ specific as well as common developmental mechanisms. As an initial step in this direction we describe a regulatory pathway involving the anti-apoptotic gene Bcl2 that controls cell survival in early thyroid development.Developmental Biology 09/2011; 359(2):163-75. · 4.07 Impact Factor -
Article: Role of EphA4 receptor signaling in thyroid development: regulation of folliculogenesis and propagation of the C-cell lineage.
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ABSTRACT: Transcriptome analysis revealed that the tyrosine kinase receptor EphA4 is enriched in the thyroid bud in mouse embryos. We used heterozygous EphA4-EGFP knock-in mice in which enhanced green fluorescent protein (EGFP) replaced the intracellular receptor domain (EphA4(+/EGFP)) to localize EphA4 protein in thyroid primordial tissues. This showed that thyroid progenitors originating in the pharyngeal floor express EphA4 at all embryonic stages and when follicles are formed in late development. Also, the ultimobranchial bodies developed from the pharyngeal pouch endoderm express EphA4, but the ultimobranchial epithelium loses the EGFP signal before it merges with the median thyroid primordium. Embryonic C cells invading the thyroid are exclusively EphA4-negative. EphA4 expression continues in the adult thyroid. EphA4 knock-out mice and EphA4-EGFP homozygous mutants are euthyroid and have a normal thyroid anatomy but display subtle histological alterations regarding number, size, and shape of follicles. Of particular interest, the pattern of follicular abnormality differs between EphA4(-/-) and EphA4(EGFP/EGFP) thyroids. In addition, the number of C cells is reduced by >50% exclusively in animals lacking EphA4 forward signaling (EphA4(EGFP/EGFP)). Heterozygous EphA4 mutants have no apparent thyroid phenotype. We conclude that EphA4 is a novel regulator of thyroid morphogenesis that impacts on postnatal development of the two endocrine cell lineages of the differentiating gland. In this process both EphA4 forward signaling (in the follicular epithelium) and reverse signaling mediated by its cognate ligand(s) (A- and/or B-ephrins expressed in follicular cells and C cells, respectively) are probably functionally important.Endocrinology 03/2011; 152(3):1154-64. · 4.46 Impact Factor -
Article: The microRNA-processing enzyme Dicer is essential for thyroid function.
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ABSTRACT: Dicer is a type III ribonuclease required for the biogenesis of microRNAs (miRNAs), a class of small non-coding RNAs regulating gene expression at the post-transcriptional level. To explore the functional role of miRNAs in thyroid gland function, we generated a thyrocyte-specific Dicer conditional knockout mouse. Here we show that development and early differentiation of the thyroid gland are not affected by the absence of Dicer, while severe hypothyroidism gradually develops after birth, leading to reduced body weight and shortened life span. Histological and molecular characterization of knockout mice reveals a dramatic loss of the thyroid gland follicular architecture associated with functional aberrations and down-regulation of several differentiation markers. The data presented in this study show for the first time that an intact miRNAs processing machinery is essential for thyroid physiology, suggesting that deregulation of specific miRNAs could be also involved in human thyroid dysfunctions.PLoS ONE 01/2011; 6(11):e27648. · 4.09 Impact Factor -
Article: Morphogenetics of early thyroid development.
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ABSTRACT: The thyroid develops from the foregut endoderm. Yet uncharacterized inductive signals specify endoderm progenitors to a thyroid cell fate that assembles in the pharyngeal floor from which the primordium buds and migrates to the final position of the gland. The morphogenetic process is regulated by both cell-autonomous (e.g. activated by NKX2-1, FOXE1, PAX8, and HHEX) and mesoderm-derived (e.g. mediated by TBX1 and fibroblast growth factors) mechanisms acting in concert to promote growth and survival of progenitor cells. The developmental role of TSH is limited to thyroid differentiation set to work after the gross anatomy of the gland is already sculptured. This review summarizes recent advances on the molecular genetics of thyroid morphogenesis put into context of endoderm developmental traits and highlights established and novel mechanisms of thyroid dysgenesis of potential relevance to congenital hypothyroidism in man.Journal of Molecular Endocrinology 01/2011; 46(1):R33-42. · 3.48 Impact Factor -
Article: Morphogenesis of the thyroid gland.
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ABSTRACT: Congenital hypothyroidism is mainly due to structural defects of the thyroid gland, collectively known as thyroid dysgenesis. The two most prevalent forms of this condition are abnormal localization of differentiated thyroid tissue (thyroid ectopia) and total absence of the gland (athyreosis). The clinical picture of thyroid dysgenesis suggests that impaired specification, proliferation and survival of thyroid precursor cells and loss of concerted movement of these cells in a distinct spatiotemporal pattern are major causes of malformation. In normal development the thyroid primordium is first distinguished as a thickening of the anterior foregut endoderm at the base of the prospective tongue. Subsequently, this group of progenitors detaches from the endoderm, moves caudally and ultimately differentiates into hormone-producing units, the thyroid follicles, at a distant location from the site of specification. In higher vertebrates later stages of thyroid morphogenesis are characterized by shape remodeling into a bilobed organ and the integration of a second type of progenitors derived from the caudal-most pharyngeal pouches that will differentiate into C-cells. The present knowledge of thyroid developmental dynamics has emerged from embryonic studies mainly in chicken, mouse and more recently also in zebrafish. This review will highlight the key morphogenetic steps of thyroid organogenesis and pinpoint which crucial regulatory mechanisms are yet to be uncovered. Considering the co-incidence of thyroid dysgenesis and congenital heart malformations the possible interactions between thyroid and cardiovascular development will also be discussed.Molecular and Cellular Endocrinology 12/2009; 323(1):35-54. · 4.19 Impact Factor -
Article: Expression of Islet1 in thyroid development related to budding, migration, and fusion of primordia.
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ABSTRACT: The LIM homeodomain transcription factor Isl1 was investigated in mouse thyroid organogenesis. All progenitor cells of the midline thyroid diverticulum and lateral primordia (ultimobranchial bodies) expressed Isl1. This pattern persisted until the growing anlagen fused at embryonic day (E) 13.5. In Isl1 null mutants thyroid progenitors expressing Nkx2.1 and Pax8 were readily specified in the anterior endoderm but the size of the thyroid rudiment was reduced. In late development, only immature C-cells expressed Isl1. In the adult gland the number of Isl1+ cells was small compared with cells expressing calcitonin. Analysis of microarray profiles indicated a higher level of Isl1 expression in medullary thyroid carcinomas than in tumors derived from follicular cells. Together, these findings suggest that Isl1 may be a novel regulator of thyroid development before terminal differentiation of the endocrine cell types. Isl1 is an embryonic C-cell precursor marker that may be relevant also in cancer developed from the mature C-cell.Developmental Dynamics 12/2008; 237(12):3820-9. · 2.54 Impact Factor -
Article: The developing mouse thyroid: embryonic vessel contacts and parenchymal growth pattern during specification, budding, migration, and lobulation.
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ABSTRACT: Normal mouse thyroid development has been revised to identify critical morphogenetic events. The early thyroid primordium associates with the aortic sac endothelium at the time of specification and budding. The vascular contact is lost after the thyroid buds from the pharyngeal endoderm, but is resumed before the gland divides to form two lobes. Lateral expansion of parenchyma takes place along the course of the third pharyngeal arch arteries. Thyroid precursor cells expressing Titf1/Nkx2.1 do not proliferate until the migration stage, implicating that progenitors likely are recruited from outside the thyroid placode. Early lobulation involves engulfment of the entire ultimobranchial bodies by the growing midline thyroid. At the same time, proliferation of the ultimobranchial body epithelium is silenced preceding the differentiation of C cells. Before folliculogenesis, thyroid lobe enlargement is reminiscent of a budding-branching-like growth pattern. It is suggested that thyroid inductive signals arise from embryonic vessels, and that this provides ideas to conceptually new pathogenetic mechanisms of thyroid dysgenesis.Developmental Dynamics 03/2006; 235(2):444-55. · 2.54 Impact Factor -
Article: Genetic deletion of sonic hedgehog causes hemiagenesis and ectopic development of the thyroid in mouse.
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ABSTRACT: Thyroid dysgenesis encountered in 85% of patients with congenital hypothyroidism is a morphologically heterogeneous condition with primarily unknown pathogenesis. Here we identify sonic hedgehog (Shh) as a novel regulator of thyroid development. In Shh knockout mice the thyroid primordium is correctly specified in the pharyngeal endoderm, but budding and dislocation are slightly delayed. In late development the thyroid fails to form a bilobed gland. Instead a single thyroid mass is found unilaterally and mostly to the left of the midline. Thyroid-specific transcription factors (TTF-1 and TTF-2) and thyroglobulin are expressed indicating terminal differentiation. Strikingly, TTF-1- and TTF-2-positive cells aberrantly develop in the presumptive trachea of Shh-/- embryos. The ectopic tissue buds ventrolaterally into the adjacent mesenchyme, and less extensively into the tracheal lumen, forming follicle-like structures that accumulate thyroglobulin. Shh mRNA is not expressed in the thyroid precursor cells at any developmental stage. The results indicate that Shh signaling indirectly governs the symmetric bilobation of the thyroid during late organogenesis. Shh also seems to repress inappropriate thyroid differentiation in nonthyroid embryonic tissues. This study provides clues to the molecular mechanisms that might be dysregulated in thyroid hemiagenesis and development of ectopic thyroid tissue outside the thyroglossal duct.American Journal Of Pathology 06/2004; 164(5):1865-72. · 4.89 Impact Factor -
Article: Nuclear accumulation of full-length and truncated adenomatous polyposis coli protein in tumor cells depends on proliferation.
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ABSTRACT: The adenomatous polyposis coli (APC) tumor suppressor is a nucleocytoplasmic protein. The nuclear accumulation of APC was recently found to vary depending on cell density, suggesting that putative APC function(s) in the nucleus is controlled by the establishment of cell contacts. We report here that the density-dependent redistribution of APC between nucleus and cytoplasm prevails in 6/6 thyroid and colorectal carcinoma cell lines. Moreover, mutated APC lacking known nuclear localization sequences had the similar distribution pattern as the full-length protein. APC invariably accumulated in the nuclei of Ki-67 expressing cells, but was largely cytoplasmic when cell cycle exit was induced by serum starvation or at high cell density. APC colocalized with beta-catenin in the nucleus only in one cell line (SW480). Also, APC maintained a predominantly nuclear position in early confluent states when cytoplasmic beta-catenin was recruited to newly formed adherens-like junctions. The results indicate that nuclear targeting of APC is driven by cell cycle entry rather than altered cell-cell contact. The ability of C-terminally truncated APC to accumulate in the nucleus suggests that nuclear import signals other than NLS1(APC) and NLS2(APC) are functionally important. Residual function(s) of N-terminal APC fragments in tumor cells carrying APC mutations might be beneficial to tumor growth and survival.Oncogene 10/2003; 22(38):6013-22. · 6.37 Impact Factor
Top co-authors
Top Journals
Institutions
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2003–2011
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University of Gothenburg
- • Department of Pathology
- • Department of Medical Biochemistry and Cell Biology
Göteborg, Vaestra Goetaland, Sweden
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2009
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Biologia e genetica molecolare
Ariano Irpino, Campania, Italy
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2004–2006
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Sahlgrenska University Hospital
Göteborg, Vaestra Goetaland, Sweden
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