title: Role of let-7b/Fzd4 axis in mitochondrial biogenesis through wnt signaling: In neonatal and adult megakaryocytes.
abstract: Megakaryocytes (MKs), a rare population of bone marrow cells, are responsible for the production of platelets. Sick neonates are predisposed to developing thrombocytopenia (platelet count <150×109/L) and neonates are affected by several megakaryocyte disorders as compared to adults.
  
  
  
  MicroRNAs (miRNAs) have been shown to crucially involve in the regulation of stem-cell differentiation in normal as well as malignant hematopoiesis, but their role in regulation of biological differences between adult and neonatal megakaryopoiesis is unknown.
  
  
  
  To study this, we cultured human cord blood (CB) and peripheral blood (PB) derived CD34+cells in the presence of thrombopoietin for 14days and collected cultures expressing>90% CD41+by flow cytometry and studied 88 miRNAs involved in stem cell development and differentiation. miRNA validation studies were performed in Dami cell line.
  
  
  
  Out of 88 miRNAs involved in stem cell development, let-7b was the only miRNA down regulated (∼10-fold) in neonates compared to adult-MKs. Let-7b has not been previously described in MKs, however reduced expression of let-7b was found in several human cancers, suggesting that it functions as a tumor suppressor. Our results showed the inhibitory effect of let-7b on wnt signaling pathway by regulating Fzd4 (frizzled family receptor 4) and thereby regulating proliferation as well as differentiation. Let-7b down regulation induced mitochondrial biogenesis and its markers PGC-1α and NRF1 during megakaryocyte development.
  
  
  
  Our findings for the first time unveil the novel role of let-7b/Fzd4 axis through wnt signaling by regulating mitochondrial biogenesis during megakaryocyte development.
authors: Stem Cells and Haematological Disorders Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, (PO) Gachibowli, Hyderabad 500046, Telangana, India.
authors: Ram Babu
authors: RB
authors: Undi
authors: Department of Biotechnology, GITAM Institute of Science, GITAM University, Visakhapatnam 530 045, Andhra Pradesh, India.
authors: Usha
authors: U
authors: Gutti
authors: Stem Cells and Haematological Disorders Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, (PO) Gachibowli, Hyderabad 500046, Telangana, India. Electronic address: guttiravi@gmail.com.
authors: Ravi Kumar
authors: RK
authors: Gutti
mesh_terms: D000328:Adult; D049109:Cell Proliferation; D005312:Fetal Blood / Q000166:cytology; D051157:Frizzled Receptors / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D001678:Organelle Biogenesis; D015854:Up-Regulation / Q000235:genetics; D060449:Wnt Signaling Pathway
chemical_list: C402930:FZD4 protein, human; D051157:Frizzled Receptors; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human
keywords: Fzd4; Let-7b; Megakaryocyte; Mitochondria; Wnt signaling