Protocadherin-α Family Is Required for Serotonergic Projections to Appropriately Innervate Target Brain Areas
Protocadherin-α Family Is Required for Serotonergic Projections to Appropriately Innervate Target Brain Areas
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DOI：
10.1523/jneurosci.5478-08.2009
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发表时间：
2009-07-22
影响因子：
5.3
通讯作者：
Yagi, Takeshi
中科院分区：
文献类型：
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作者：
Katori, Shota;Hamada, Shun;Yagi, Takeshi
脑干中缝核的血清素能轴突投射到大脑的每个区域，在那里它们通过广泛的末端分支建立联系。这种5 -羟色胺能神经支配有助于各种正常行为和精神障碍。原钙粘蛋白- α (Pcdha)家族由14个钙粘蛋白相关分子组成，这些分子是由单个基因簇产生的。我们发现Pcdhas在血清素能神经元中强烈表达。为了阐明它们的作用，我们检测了缺乏Pcdha细胞质区域编码外显子的小鼠突变体（Pcdha(Delta CR/Delta CR)）中的5 -羟色胺能纤维，这些外显子在该基因簇中是常见的。出生后第1周，5 -羟色胺能纤维在Pcdha（Delta CR/Delta CR）小鼠体内的分布模式与野生型相似，但到3周龄时，5 -羟色胺能轴突末梢完成了其分支，其投射分布出现异常。在某些靶区，特别是苍白球和黑质，突变体中5 -羟色胺轴突末端的正常均匀分布在每个区域的外围密集，而在中心稀疏。海马空隙层-分子区5 -羟色胺神经分布较野生型密集，海马齿状回和尾壳核区5 -羟色胺神经分布较少。总之，这些异常表明Pcdha蛋白在血清素能投射的后期成熟中很重要。对编码胞质尾部的选择性剪接外显子的进一步检查表明，a型（而不是b型）胞质尾部对血清素能投射的正常发育至关重要。
Serotonergic axons from the raphe nuclei in the brainstem project to every region of the brain, where they make connections through their extensive terminal arborizations. This serotonergic innervation contributes to various normal behaviors and psychiatric disorders. The protocadherin-alpha (Pcdha) family of clustered protocadherins consists of 14 cadherin-related molecules generated from a single gene cluster. We found that the Pcdhas were strongly expressed in the serotonergic neurons. To elucidate their roles, we examined serotonergic fibers in a mouse mutant (Pcdha(Delta CR/Delta CR)) lacking the Pcdha cytoplasmic region-encoding exons, which are common to the gene cluster. In the first week after birth, the distribution pattern of serotonergic fibers in Pcdha(Delta CR/Delta CR) mice was similar to wild-type, but by 3 weeks of age, when the serotonergic axonal termini complete their arborizations, the distribution of the projections was abnormal. In some target regions, notably the globus pallidus and substantia nigra, the normally even distribution of serotonin axonal terminals was, in the mutants, dense at the periphery of each region, but sparse in the center. In the stratum lacunosum-moleculare of the hippocampus, the mutants showed denser serotonergic innervation than in wild-type, and in the dentate gyrus of the hippocampus and the caudate-putamen, the innervation was sparser. Together, the abnormalities suggested that Pcdha proteins are important in the late-stage maturation of serotonergic projections. Further examination of alternatively spliced exons encoding the cytoplasmic tail showed that the A-type (but not the B-type) cytoplasmic tail was essential for the normal development of serotonergic projections.