Foxo1 is a downstream effector of Isl1 in direct pathway striatal projection neuron development within the embryonic mouse telencephalon.
Foxo1 is a downstream effector of Isl1 in direct pathway striatal projection neuron development within the embryonic mouse telencephalon.
复制标题
DOI：
10.1016/j.mcn.2017.02.003
复制
发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
Campbell K
中科院分区：
文献类型：
--
作者：
Waclaw RR;Ehrman LA;Merchan-Sala P;Kohli V;Nardini D;Campbell K
最近的研究表明，LIM-homeodomain转录因子Isl 1是必需的直接通路纹状体黑质神经元在胚胎发育过程中的生存和分化。Isl 1在这些过程中的下游效应子目前尚不清楚。我们在这里显示，Foxo 1，一个转录因子，已牵连在细胞存活，表达在纹状体投射神经元（SPN），来自Isl 1谱系（即直接途径SPN）。此外，Isl 1条件性敲除（cKO）显示Foxo 1表达在E15.5时严重丧失，到E18.5时适度恢复。虽然Foxo 1在胚胎阶段富集在直接途径SPN中，但在出生后的时间点，它在直接和间接途径SPN中表达，如通过在Drd 1-EGFP和Drd 2-EGFP BAC转基因小鼠中与EGFP共定位所证明的。转录因子Nkx2.1标记的纹状体中间神经元中未检测到Foxo 1。使用Dlx 5/6-CIE的Foxo 1的条件性敲除导致在E15.5的胚胎纹状体内SPN标记Darpp-32以及直接途径SPN标记Ebf 1和Zfp 521的表达降低。然而，这种表型在条件突变体中通过E18.5改善。有趣的是，Foxo家族成员Foxo 3和Foxo 6在Foxo 1 cKO中在胚胎晚期仍然表达，不像Isl 1 cKO，其中Foxo 1/3/6以及Foxo 1/3靶标Bach 2都减少。综上所述，这些发现表明，Foxo调节的途径是下游的Isl 1的生存和/或分化的直接途径SPN。
Recent studies have shown that the LIM-homeodomain transcription factor Isl1 is required for the survival and differentiation of direct pathway striatonigral neurons during embryonic development. The downstream effectors of Isl1 in these processes are presently unknown. We show here that Foxo1, a transcription factor that has been implicated in cell survival, is expressed in striatal projection neurons (SPNs) that derive from the Isl1 lineage (i.e. direct pathway SPNs). Moreover, Isl1 conditional knockouts (cKOs) show a severe loss of Foxo1 expression at E15.5 with a modest recovery by E18.5. Although Foxo1 is enriched in the direct pathway SPNs at embryonic stages, it is expressed in both direct and indirect pathway SPNs at postnatal time points as evidenced by co-localization with EGFP in both Drd1-EGFP and Drd2-EGFP BAC transgenic mice. Foxo1 was not detected in striatal interneurons as marked by the transcription factor Nkx2.1. Conditional knockout of Foxo1 using Dlx5/6-CIE results in reduced expression of the SPN marker Darpp-32, as well as in the direct pathway SPN markers Ebf1 and Zfp521 within the embryonic striatum at E15.5. However, this phenotype improves in the conditional mutants by E18.5. Interestingly, the Foxo family members, Foxo3 and Foxo6, remain expressed at late embryonic stages in the Foxo1 cKOs unlike the Isl1 cKOs where Foxo1/3/6 as well as the Foxo1/3 target Bach2 are all reduced. Taken together, these findings suggest that Foxo-regulated pathways are downstream of Isl1 in the survival and/or differentiation of direct pathway SPNs.