A quantitative trait locus on chromosome 4 affects cycling of hematopoietic stem and progenitor cells through regulation of TGF-beta 2 responsiveness.
A quantitative trait locus on chromosome 4 affects cycling of hematopoietic stem and progenitor cells through regulation of TGF-beta 2 responsiveness.
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4 号染色体上的数量性状基因座通过调节 TGF-β2 反应性影响造血干细胞和祖细胞的循环。
DOI：
10.4049/jimmunol.181.9.5904
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发表时间：
2008-11-01
影响因子：
4.4
通讯作者：
Snoeck, Hans-Willem
中科院分区：
文献类型：
--
作者：
Avagyan, Serine;Glouchkova, Ludmila;Choi, Juhyun;Snoeck, Hans-Willem
造血干细胞和祖细胞(HSPC)亚群受到大量数量遗传变异的影响。我们先前已经证明，转化生长因子-β2(转化生长因子-β2)在低浓度时促进Flt3配体诱导的HSPC的生长，而在较高浓度时有效地抑制β的增殖。这种体外增强效应受制于数量遗传变异，其数量性状基因座(QTL)被初步定位于Chr.4。Tgfb2+/-小鼠有一个较小且循环较慢的HSPC隔室，其连续再繁殖能力降低，对高剂量5-氟尿嘧啶(5-FU)的致死作用较不敏感。为了明确地证明这些表型可以归因于转化生长因子-β2对体外观察到的HSPC增殖的促进作用，因此也受到小鼠品系的影响，我们产生了同源基因小鼠，其中Chr.4的端粒区域从Dba/2导入C57BL/6小鼠。在这些小鼠中，转化生长因子-β2对Flt3信号的促进作用被取消，但不是高浓度转化生长因子-β2的一般抑制增殖作用，证实了这个QTL的位置，我们将其命名为tb2r1。这些小鼠与Tgfb2+/-小鼠共享一个更小且循环更慢的HSPC隔室，增加了5-FU抵抗，但没有降低序列再繁殖能力。Tgfb2+/-与同基因小鼠的表型一致性表明，HSPC的频率和周期受tb2r1的调控，而在chr.4端粒区域的一个额外的QTL可能调节HSCs的序列再繁殖能力。
The hematopoietic stem and progenitor cell (HSPC) compartment is subject to extensive quantitative genetic variation. We have previously shown that transforming growth factor-beta 2 (TGF-β2) at low concentrations enhances flt3 ligand induced growth of HSPCs, while it is potently antiproliferative at higher concentrations. This in vitro enhancing effect was subject to quantitative genetic variation, for which a quantitative trait locus (QTL) was tentatively mapped to chr.4. Tgfb2+/- mice have a smaller and more slowly cycling HSPC compartment, which has a decreased serial repopulation capacity, and are less susceptible to the lethal effect of high doses of 5-fluorouracil (5-FU). To unequivocally demonstrate that these phenotypes can be attributed to the enhancing effect of TGF-β2 on HSPC proliferation observed in vitro and are therefore subject to mouse strain-dependent variation as well, we generated congenic mice where the telomeric region of chr.4 was introgressed from DBA/2 into C57BL/6 mice. In these mice, the enhancing effect of TGF-β2 on flt3 signaling, but not the generic antiproliferative effect of high concentrations of TGF-β2, was abrogated, confirming the location of this QTL, which we named tb2r1, on chr.4. These mice shared a smaller and more slowly cycling HSPC compartment, increased 5-FU resistance but not a decreased serial repopulation capacity with Tgfb2+/- mice. The concordance of phenotypes between Tgfb2+/- and congenic mice indicates that HSPC frequency and cycling are regulated by tb2r1, while an additional QTL in the telomeric region of chr.4 may regulate the serial repopulation capacity of HSCs.
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影响因子：
4.4
作者：
Henckaerts, E;Langer, JC;Snoeck, HW
通讯作者：
Snoeck, HW
影响因子：
4.4
作者：
Kwon, BS;Hurtado, JC;Vinay, DS
通讯作者：
Vinay, DS
DOI：
10.1084/jem.186.4.529
发表时间：
1997-08-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
de Haan G;Van Zant G
通讯作者：
Van Zant G
影响因子：
30.8
作者：
Bystrykh, L;Weersing, E;de Haan, G
通讯作者：
de Haan, G
影响因子：
2.6
作者：
Chen, JC;Astle, CM;Harrison, DE
通讯作者：
Harrison, DE