Ventralized dorsal telencephalic progenitors in Pax6 mutant mice generate GABA interneurons of a lateral ganglionic eminence fate
Ventralized dorsal telencephalic progenitors in Pax6 mutant mice generate GABA interneurons of a lateral ganglionic eminence fate
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DOI：
10.1073/pnas.0500819102
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发表时间：
2005-05-17
影响因子：
11.1
通讯作者：
O'Leary, DDM
中科院分区：
文献类型：
--
作者：
Kroll, TT;O'Leary, DDM
转录因子Pax6由端脑背侧脑室带(VZ)的前体细胞表达，产生所有皮质谷氨酸能神经元，但不表达于内侧神经节隆起(MGE)或外侧神经节隆起(LGE)的前体细胞，内侧神经节隆起产生皮质GABA能中间神经元(GABA INS)，外侧神经节隆起产生通常迁移到嗅球的GABA IN。我们发现，在围产期，缺乏功能性Pax6蛋白的Pax6(Sey/Sey)小鼠在dtel内有大的硬膜下异位，腹侧端脑由dtel中发现的异常室旁异位产生的细胞流连接。软膜下和室旁异位以及连接细胞流由有丝分裂后神经元组成，表达具有LGE命运特征的GABA INS标记。标记分析表明，在Pax6突变体中，dtel VZ的祖细胞逐渐腹腔化，获得通常仅限于GE祖细胞的调控基因的表达；在中期神经发生时，整个dtel VZ呈现腹腔化。DTELVZ的这种内侧化与其表面的GABA INS标记的表达平行，表明它异地产生GABA INS，导致它们的异位，由于谷氨酸能神经元的产生减少，导致皮质板变薄。遗传谱系追踪表明，组成异位的GABA ins来自dtel VZ中产生的皮层Emx1谱系，明确表明dtel的祖先和后代在Pax6突变体中获得了腹侧的Ge，命运。因此，Pax6为GABA ins划定了合适的增殖区，并通过抑制dtel前体和后代的腹侧命运来调节它们的数量和分布。
The transcription factor Pax6 is expressed by progenitors in the ventricular zone (VZ) of dorsal telencephalon (dTel), which generate all cortical glutamatergic neurons, but not by progenitors in the medial ganglionic eminence (MGE), which generate cortical GABAergic interneurons (GABA INs), or the lateral ganglionic eminence (LGE), which generate GABA INs that normally migrate to the olfactory bulb. We show that perinatally, Pax6(sey/sey) mice, which lack functional Pax6 protein, have large subpial ectopias in dTel and ventral telencephalon connected by cell streams arising from an aberrant paraventricular ectopia found throughout dTel. The subpial and paraventricular ectopias and connecting cell streams are comprised of postmitotic neurons expressing markers for GABA INs characteristic of a LGE fate. Marker analyses show that dTel VZ progenitors in Pax6 mutants are progressively ventralized, acquiring expression of regulatory genes normally limited to GE progenitors; by midneurogenesis, the entire dTel VZ exhibits ventralization. This ventralization of the dTel VZ is paralleled by the expression of markers for GABA INs superficial to it, suggesting that it ectopically produces GABA INs, leading to their ectopias and a thinner cortical plate due to diminished production of glutamatergic neurons. Genetic lineage tracing demonstrates that the GABA INs comprising the ectopias are from a cortical Emx1 lineage generated in the dTel VZ, definitively showing that dTel progenitors and progeny acquire a ventral, GE, fate in Pax6 mutants. Thus, Pax6 delimits the appropriate proliferative zone for GABA INs and regulates their numbers and distributions by repressing the ventral fates of dTel progenitors and progeny.