PMID- 21304100
OWN - NLM
STAT- MEDLINE
DCOM- 20110621
LR  - 20211203
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 117
IP  - 15
DP  - 2011 Apr 14
TI  - Developmental differences in megakaryocytopoiesis are associated with 
      up-regulated TPO signaling through mTOR and elevated GATA-1 levels in neonatal 
      megakaryocytes.
PG  - 4106-17
LID - 10.1182/blood-2010-07-293092 [doi]
AB  - 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.
FAU - Liu, Zhi-Jian
AU  - Liu ZJ
AD  - Division of Newborn Medicine, Children's Hospital Boston, Boston, MA, USA.
FAU - Italiano, Joseph Jr
AU  - Italiano J Jr
FAU - Ferrer-Marin, Francisca
AU  - Ferrer-Marin F
FAU - Gutti, Ravi
AU  - Gutti R
FAU - Bailey, Matthew
AU  - Bailey M
FAU - Poterjoy, Brandon
AU  - Poterjoy B
FAU - Rimsza, Lisa
AU  - Rimsza L
FAU - Sola-Visner, Martha
AU  - Sola-Visner M
LA  - eng
GR  - R01 HL069990/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110208
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (GATA1 Transcription Factor)
RN  - 0 (GATA1 protein, human)
RN  - 0 (Transcription Factors)
RN  - 9014-42-0 (Thrombopoietin)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
CIN - Blood. 2011 Apr 14;117(15):3940-1. PMID: 21493803
MH  - Cell Differentiation/physiology
MH  - Fetal Blood/cytology
MH  - GATA1 Transcription Factor/*metabolism
MH  - Hematopoietic Stem Cells/cytology/*metabolism
MH  - Humans
MH  - Infant, Newborn
MH  - Megakaryocytes/*metabolism/ultrastructure
MH  - Microscopy, Electron, Transmission
MH  - Signal Transduction/physiology
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Thrombopoiesis/*physiology
MH  - Thrombopoietin/*metabolism
MH  - Transcription Factors/metabolism
MH  - Up-Regulation/physiology
PMC - PMC3087534
EDAT- 2011/02/10 06:00
MHDA- 2011/06/22 06:00
PMCR- 2012/04/14
CRDT- 2011/02/10 06:00
PHST- 2011/02/10 06:00 [entrez]
PHST- 2011/02/10 06:00 [pubmed]
PHST- 2011/06/22 06:00 [medline]
PHST- 2012/04/14 00:00 [pmc-release]
AID - S0006-4971(20)45280-2 [pii]
AID - 2010/293092 [pii]
AID - 10.1182/blood-2010-07-293092 [doi]
PST - ppublish
SO  - Blood. 2011 Apr 14;117(15):4106-17. doi: 10.1182/blood-2010-07-293092. Epub 2011 
      Feb 8.