Departments of Biochemistry and Molecular Biology and Medical Genetics, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Department of Pathology and Laboratory Medicine, Southern Alberta Cancer Research Institute, University of Calgary, Alberta T2N 4N1, Canada, Programs in Cell Biology, and Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto M5G 1L7, Canada, Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York 13210, Institute of Medical Science and Department of Molecular Genetics, University of Toronto, Toronto M5S 1A8, Canada, and Division of Molecular Neurobiology, National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom.
J Neurosci. 2014 Jan 8;34(2):539-53. doi: 10.1523/JNEUROSCI.0614-13.2014.
The three-layered piriform cortex, an integral part of the olfactory system, processes odor information relayed by olfactory bulb mitral cells. Specifically, mitral cell axons form the lateral olfactory tract (LOT) by targeting lateral olfactory tract (lot) guidepost cells in the piriform cortex. While lot cells and other piriform cortical neurons share a pallial origin, the factors that specify their precise phenotypes are poorly understood. Here we show that in mouse, the proneural genes Neurog1 and Neurog2 are coexpressed in the ventral pallium, a progenitor pool that first gives rise to Cajal-Retzius (CR) cells, which populate layer I of all cortical domains, and later to layer II/III neurons of the piriform cortex. Using loss-of-function and gain-of-function approaches, we find that Neurog1 has a unique early role in reducing CR cell neurogenesis by tempering Neurog2's proneural activity. In addition, Neurog1 and Neurog2 have redundant functions in the ventral pallium, acting in two phases to first specify a CR cell fate and later to specify layer II/III piriform cortex neuronal identities. In the early phase, Neurog1 and Neurog2 are also required for lot cell differentiation, which we reveal are a subset of CR neurons, the loss of which prevents mitral cell axon innervation and LOT formation. Consequently, mutation of Trp73, a CR-specific cortical gene, results in lot cell and LOT axon displacement. Neurog1 and Neurog2 thus have unique and redundant functions in the piriform cortex, controlling the timing of differentiation of early-born CR/lot cells and specifying the identities of later-born layer II/III neurons.
三层梨状皮质是嗅觉系统的一个组成部分，它处理嗅球僧帽细胞传递的气味信息。具体来说，僧帽细胞轴突通过靶向梨状皮质中的外侧嗅束（LOT）引导细胞形成外侧嗅束（LOT）。虽然 LOT 细胞和其他梨状皮质神经元具有相同的皮层起源，但决定其精确表型的因素尚不清楚。在这里，我们发现在小鼠中，神经调节蛋白 1（Neurog1）和神经调节蛋白 2（Neurog2）这两个神经前体细胞基因在腹侧皮质中共同表达，腹侧皮质是一个祖细胞池，首先产生 Cajal-Retzius（CR）细胞，这些细胞分布在所有皮质区域的 I 层，然后产生梨状皮质的 II/III 层神经元。通过功能丧失和功能获得的方法，我们发现 Neurog1 通过调节 Neurog2 的神经前体细胞活性，在减少 CR 细胞神经发生方面具有独特的早期作用。此外，Neurog1 和 Neurog2 在腹侧皮质中具有冗余功能，在两个阶段发挥作用，首先确定 CR 细胞命运，然后确定 II/III 层梨状皮质神经元身份。在早期阶段，Neurog1 和 Neurog2 也需要 LOT 细胞分化，我们发现 LOT 细胞是 CR 神经元的一个子集，其缺失阻止了僧帽细胞轴突的神经支配和 LOT 的形成。因此，CR 特异性皮质基因 Trp73 的突变导致 LOT 细胞和 LOT 轴突移位。因此，Neurog1 和 Neurog2 在梨状皮质中具有独特和冗余的功能，控制早期出生的 CR/LOT 细胞分化的时间，并指定后来出生的 II/III 层神经元的身份。
