Lkb1 regulates granule cell migration and cortical folding of the cerebellar cortex.
Lkb1 regulates granule cell migration and cortical folding of the cerebellar cortex.
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DOI：
10.1016/j.ydbio.2017.09.036
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发表时间：
2017-12-01
影响因子：
2.7
通讯作者：
Chiang C
中科院分区：
文献类型：
--
作者：
Ryan KE;Kim PS;Fleming JT;Brignola E;Cheng FY;Litingtung Y;Chiang C
小脑的生长和叶化需要刺猬驱动的颗粒细胞前体(GCP)在外部颗粒层(EGL)的增殖。然而，GCP增殖的增加或延长通常不会引起异位皱折，这表明在小脑发育过程中，额外的决定因素控制着皮质的扩张和叶片化。在这里，我们发现在GCPs中丝氨酸-苏氨酸激酶LKB1(Lkb1)的遗传缺失增加了小脑皮质的大小和叶片化，与增殖或Hedgehog信号的变化无关。这一发现是出乎意料的，因为之前已经证明Lkb1在培养细胞中对Hedgehog途径的激活至关重要。与GCPs的增殖率不变一致，Lkb1突变体的皮质扩张伴随着EGL的变薄。与野生型对照相比，突变体中的细胞分裂平面保持不变，该平面参与了从上皮表面扩张到人类皮质回变的各种过程。然而，我们发现Lkb1突变体表现出有丝分裂后GCP的延迟径向迁移，这与皮质大小的增加相一致，这表明异常的细胞迁移可能有助于皮质的扩张和叶片化的增加。综上所述，我们的结果揭示了Lkb1在以非刺猬依赖的方式调节小脑皮质大小和叶化方面的重要作用。
Cerebellar growth and foliation require the Hedgehog-driven proliferation of granule cell precursors (GCPs) in the external granule layer (EGL). However, that increased or extended GCP proliferation generally does not elicit ectopic folds suggests that additional determinants control cortical expansion and foliation during cerebellar development. Here, we find that genetic loss of the serine-threonine kinase Liver Kinase B1 (Lkb1) in GCPs increased cerebellar cortical size and foliation independent of changes in proliferation or Hedgehog signaling. This finding is unexpected given that Lkb1 has previously shown to be critical for Hedgehog pathway activation in cultured cells. Consistent with unchanged proliferation rate of GCPs, the cortical expansion of Lkb1 mutants is accompanied by thinning of the EGL. The plane of cell division, which has been implicated in diverse processes from epithelial surface expansions to gyrification of the human cortex, remains unchanged in the mutants when compared to wild-type controls. However, we find that Lkb1 mutants display delayed radial migration of post-mitotic GCPs that coincides with increased cortical size, suggesting that aberrant cell migration may contribute to the cortical expansion and increase foliation. Taken together, our results reveal an important role for Lkb1 in regulating cerebellar cortical size and foliation in a Hedgehog-independent manner.
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