Impact of GDNF family receptor alpha1 for the development of cortical GABAergic interneurons in the mouse brain

GABA能抑制性中间神经元形成大脑皮层的重要部分，因为它们同步锥体细胞的动作。控制抑制性中间神经元多样化和分配到不同皮层区域的机制仍然知之甚少。皮质中间神经元的起源是内侧和尾侧神经节隆起（MGE和CGE），以及视前区（POA），但以钙结合蛋白小白蛋白（PV）表达为特征的中间神经元主要产生于MGE。GDNF及其受体GFR α 1参与GABA能前体的发育，但由于肾发育不全导致GFR α 1基因敲除小鼠的致死表型，阻碍了对它们在出生后发育中作用的分析。仅在GFR α 1相互作用伴侣RET阴性的细胞中缺乏GFR α 1的小鼠突变体（仅顺式小鼠）在皮质中显示“PV孔”，即主要在视觉和额叶皮质区域中发现的没有任何PV表达的区域。本研究的目的之一是证明GFRalpha 1阳性的MGE细胞在胚胎发育成PV阳性的皮质中间神经元出生后。这将通过遗传命运作图来实现，因为MGE前体被认为在迁移到皮质时失去GFR α 1表达。此外，将研究导致仅顺式小鼠中缺陷的机制。将胚胎MGE前体移植到出生后早期的顺式皮质中将允许区分细胞自主机制和非细胞自主机制。此外，将对条件性GFR α 1敲除小鼠（GABA能中间神经元中存在特异性GFR α 1缺失）进行分析，以进一步了解GFR α 1受体在中间神经元发育和功能中的作用。

GABAergic inhibitory interneurons form an important part of the cerebral cortex as they synchronize actions of pyramidal cells. The mechanisms controlling inhibitory interneuron diversification and allocation to distinct cortical areas remain poorly understood. The origins of cortical interneurons are the medial and caudal ganglionic eminences (MGE and CGE), as well as the preoptic area (POA), but interneurons characterized by the expression of the calcium-binding protein parvalbumin (PV) are predominantly generated in the MGE. GDNF and its receptor GFRalpha1 have been implicated in the development of GABAergic precursors, but the analysis of their roles in postnatal development is hampered by the lethal phenotype of GFRalpha1 knockout mice due to kidney agenesis. Mouse mutants that lack GFRalpha1 only in cells that are negative for the GFRalpha1 interaction partner RET (cis-only mice), show „PV holes“ in the cortex, i.e. regions without any PV expression that are mostly found in visual and frontal cortex areas. One aim of this study is to prove that GFRalpha1-positive MGE cells in the embryo develop into PV-positive cortical interneurons postnatally. This shall be achieved by genetic fate mapping, as MGE precursors are thought to lose GFRalpha1 expression while migrating to the cortex. In addition, the mechanism which leads to defects in the cis-only mouse will be investigated. Transplantation of embryonic MGE precursors into the early postnatal cis-only cortex will allow distinguishing between a cell-autonomous and a non-cell-autonomous mechanism. Furthermore, analysis of conditional GFRalpha1 knockout mice - with specific GFRalpha1 deletion in GABAergic interneurons - will be performed in order to gain additional insight into the roles of the GFRalpha1 receptor in interneuron development and function.