title: Developmental differences in megakaryocytopoiesis are associated with up-regulated TPO signaling through mTOR and elevated GATA-1 levels in neonatal megakaryocytes.
abstract: Multiple observations support the existence of developmental differences in megakaryocytopoiesis. We have previously shown that neonatal megakaryocyte (MK) progenitors are hyperproliferative and give rise to MKs smaller and of lower ploidy than adult MKs. Based on these characteristics, neonatal MKs have been considered immature. The molecular mechanisms underlying these differences are unclear, but contribute to the pathogenesis of disorders of neonatal megakaryocytopoiesis. In the present study, we demonstrate that low-ploidy neonatal MKs, contrary to traditional belief, are more mature than adult low-ploidy MKs. These mature MKs are generated at a 10-fold higher rate than adult MKs, and result from a developmental uncoupling of proliferation, polyploidization, and terminal differentiation. This pattern is associated with up-regulated thrombopoietin (TPO) signaling through mammalian target of rapamycin (mTOR) and elevated levels of full-length GATA-1 and its targets. Blocking of mTOR with rapamycin suppressed the maturation of neonatal MKs without affecting ploidy, in contrast to the synchronous inhibition of polyploidization and cytoplasmic maturation in adult MKs. We propose that these mechanisms allow fetuses/neonates to populate their rapidly expanding bone marrow and intravascular spaces while maintaining normal platelet counts, but also set the stage for disorders restricted to fetal/neonatal MK progenitors, including the Down syndrome-transient myeloproliferative disorder and the thrombocytopenia absent radius syndrome.
authors.affiliation: Division of Newborn Medicine, Children's Hospital Boston, Boston, MA, USA.
authors.forename: Zhi-Jian
authors.initials: ZJ
authors.lastname: Liu
authors.forename: Joseph
authors.initials: J
authors.lastname: Italiano
authors.forename: Francisca
authors.initials: F
authors.lastname: Ferrer-Marin
authors.forename: Ravi
authors.initials: R
authors.lastname: Gutti
authors.forename: Matthew
authors.initials: M
authors.lastname: Bailey
authors.forename: Brandon
authors.initials: B
authors.lastname: Poterjoy
authors.forename: Lisa
authors.initials: L
authors.lastname: Rimsza
authors.forename: Martha
authors.initials: M
authors.lastname: Sola-Visner
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D005312:Fetal Blood / Q000166:cytology; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D008533:Megakaryocytes / Q000378:metabolism* / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D034061:Thrombopoiesis / Q000502:physiology*; D013926:Thrombopoietin / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D014157:Transcription Factors; D013926:Thrombopoietin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases