Verheyden Jamie M, Lewandoski Mark, Deng Chuxia, Harfe Brian D, Sun Xin
Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA.
Development. 2005 Oct;132(19):4235-45. doi: 10.1242/dev.02001. Epub 2005 Aug 24.
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.
先前的研究表明成纤维细胞生长因子受体1（FGFR1）参与肢体发育。然而，其作用的确切性质和复杂性尚未明确。在此，我们通过使用两种不同的表达Cre重组酶的品系对Fgfr1进行条件性失活，来剖析其在小鼠肢体中的功能。使用T（短尾）-cre品系导致在肢体起始阶段所有肢体芽间充质（LBM）细胞中的Fgfr1失活。该突变体揭示了FGFR1在肢体发育两个阶段中的功能。在新生肢体芽中，FGFR1促进近远轴（PD）的长度，同时限制另外两个轴的尺寸。它在这一早期阶段限制LBM细胞数量方面也发挥了意想不到的作用。在肢体生长后期，FGFR1通过维持细胞存活对骨骼前体细胞群体的扩增至关重要。使用携带音猬因子（cre）（Shh（cre））等位基因的小鼠导致后LBM细胞中的Fgfr1失活。该突变体使我们能够在不干扰肢体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 autopod 模式形成过程中，FGFR1可能通过对Shh表达的细胞自主调节来影响指（趾）的数量和特征。我们对这两种Fgfr1条件性突变体的研究阐明了FGFR1在肢体芽形成、生长和模式形成中的多种作用。
