In the eel ovary, the expression of growth differentiation factor-9 (Gdf9) appears to be largely confined to the germ cell in early stages of oogenesis. However, both the target tissue and the function of Gdf9 in fish remain unknown. This study aimed to describe the abundance and localization of activin receptor-like kinase-5 (Alk5) and bone morphogenetic protein receptor type II (Bmpr2), which together mediate the Gdf9 signal, in the ovary of a basal teleost, the shortfinned eel, Anguilla australis, during early folliculogenesis. The cDNA encoding eel alk5 and bmpr2 genes were cloned, characterized and the transcript abundances of these receptors quantified by quantitative real-time PCR. Ovarian transcript abundance for both receptors, along with that of gdf9 and of its paralogue bmp15, increased from the previtellogenic to early vitellogenic stage. Localization of receptor mRNAs by in situ hybridization revealed that these receptors are located in the somatic cells surrounding the oocyte. Furthermore, tissue distribution analysis showed that the expression of alk5 and bmpr2 were highest in ovary and thyroid, respectively. Unexpectedly, however, bmpr2 mRNA levels were lower in the ovary than in any of the other 17 tissues examined, and indeed, lower than ovarian gdf9 transcript abundance. These findings, together with the ovarian expression pattern of Gdf9, suggest that Gdf9, and conceivably, Bmp15, from the oocyte can signal through receptors that are located on the somatic cells surrounding the oocyte; this, in turn, facilitates elucidation of the function of these growth factors during oogenesis in teleost fish.
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http://dx.doi.org/10.1016/j.cbpb.2020.110509 | DOI Listing |
J Clin Invest
January 2025
Department of Laboratory Medicine, Division of Translational Cancer Researc, Lund University Cancer Centre, Lund University, Lund, Sweden.
The biology centered around the TGF-beta type I receptor Activin Receptor-Like Kinase (ALK)1 (encoded by ACVRL1) has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than two decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages (TAMs) that, by virtue of their unanticipated Acvrl1 expression, are effector targets for adjuvant anti-angiogenic immunotherapy in mouse models of metastatic breast cancer. The combinatorial benefit depended on ALK1-mediated modulation of the differentiation potential of bone marrow-derived granulocyte-macrophage progenitors, the release of CD14+ monocytes into circulation, and their eventual extravasation.
View Article and Find Full Text PDFLeuk Lymphoma
December 2024
Blood Cancer Institute, Department of Oncology, Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA.
Overactivation of the Transforming Growth Factor Beta (TGF-β) pathway is implicated in the pathogenesis of cytopenias in Myelodysplastic syndromes (MDS) and Acute Myeloid Leukemia (AML). IOA-359 and IOA-360 are potent small molecule inhibitors of the TGF-beta Receptor type I kinase (TGF-βRI, also referred to as ALK5, activin receptor-like kinase 5) that abrogate SMAD phosphorylation in hematopoietic cell lines. Both inhibitors were able to inhibit TGF-β mediated gene transcription at specific doses.
View Article and Find Full Text PDFEur J Drug Metab Pharmacokinet
December 2024
Department of Early Development, Incyte Corporation, Wilmington, DE, USA.
Background And Objectives: The oral, potent, and highly selective activin receptor-like kinase 2 (ALK2) inhibitor zilurgisertib (INCB000928) is in development as a treatment for fibrodysplasia ossificans progressiva (FOP), and for anemia due to myelofibrosis, myelodysplastic syndromes, and multiple myeloma. Saliva is an attractive alternative to blood for drug monitoring and pharmacokinetic analysis, as it is non-invasive to retrieve. This is beneficial for patients, such as those with FOP, for whom blood draws can be challenging due to soft tissue damage susceptibility that can cause progressive heterotopic ossification, and for whom tourniquet time and blood draws must be minimized.
View Article and Find Full Text PDFBackground: Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder characterized by arteriovenous malformations (AVMs). Loss-of-function mutations in Activin receptor-like kinase 1 (ALK1) cause type 2 HHT and knockout (KO) mice develop AVMs due to overactivation of VEGFR2/PI3K/AKT signaling pathways. However, the full spectrum of signaling alterations in mutants remains unknown and means to combat AVM formation in patients are yet to be developed.
View Article and Find Full Text PDFHereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder with manifestations including severe nose bleeding and microhemorrhage in brains. Despite being the second most common inherited bleeding disorder, the pathophysiological mechanism underlying HHT-associated hemorrhage is poorly understood. HHT pathogenesis is thought to follow a Knudsonian two-hit model, requiring a second somatic mutation for lesion formation.
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