Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning
Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning
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DOI：
10.1242/dev.02001
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发表时间：
2005-10-01
期刊：
影响因子：
4.6
通讯作者：
Sun, X
中科院分区：
文献类型：
--
作者：
Verheyden, JM;Lewandoski, M;Sun, X
先前的研究表明成纤维细胞生长因子受体 1 (FGFR1) 与肢体发育有关。然而，其作用的确切性质和复杂性尚未确定。在这里，我们通过使用两种不同的 Cre 重组酶表达系条件性灭活 Fgfr1 来剖析 Fgfr1 在小鼠肢体中的功能。 T (brachyury)-cre 系的使用导致肢体起始过程中所有肢芽间充质 (LBM) 细胞中的 Fgfr1 失活。该突变体揭示了 FGFR1 在肢体发育的两个阶段中的功能。在新生肢芽中，FGFR1 促进近远轴 (PD) 轴的长度，同时限制其他两个轴的尺寸。它还在限制早期阶段的 LBM 细胞数量方面发挥了意想不到的作用。随后在肢体生长过程中，FGFR1 通过维持细胞存活对于骨骼前体细胞群的扩张至关重要。使用携带声波刺猬(cre) (Shh(cre)) 等位基因的小鼠导致后LBM 细胞中Fgfr1 失活。该突变体使我们能够在不干扰肢芽生长的情况下测试 Fgfr1 在基因表达调控中的作用。我们的数据表明，在自动足模式形成过程中，FGFR1 可能通过细胞自主调节 Shh 表达来影响数字数量和身份。我们对这两种 Fgfr1 条件突变体的研究阐明了 FGFR1 在肢芽建立、生长和模式形成中的多重作用。
Previous studies have implicated fibroblast growth factor receptor 1 (FGFR1) in limb development. However, the precise nature and complexity of its role have not been defined. Here, we dissect Fgfr1 function in mouse limb by conditional inactivation of Fgfr1 using two different Cre recombinase-expressing lines. Use of the T (brachyury)-cre line led to Fgfr1 inactivation in all limb bud mesenchyme (LBM) cells during limb initiation. This mutant reveals FGFR1 function in two phases of limb development. In a nascent limb bud, FGFR1 promotes the length of the proximodistal (PD) axis while restricting the dimensions of the other two axes. It also serves an unexpected role in limiting LBM cell number in this early phase. Later on during limb outgrowth, FGFR1 is essential for the expansion of skeletal precursor population by maintaining cell survival. Use of mice carrying the sonic hedgehog(cre) (Shh(cre)) allele led to Fgfr1 inactivation in posterior LBM cells. This mutant allows us to test the role of Fgfr1 in gene expression regulation without disturbing limb bud growth. Our data show that during autopod patterning, FGFR1 influences digit number and identity, probably through cell-autonomous regulation of Shh expression. Our study of these two Fgfr1 conditional mutants has elucidated the multiple roles of FGFR1 in limb bud establishment, growth and patterning.