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J Neurosci. 2014 Jan 8;34(2):539-53. doi: 10.1523/JNEUROSCI.0614-13.2014.

Neurog1 and Neurog2 control two waves of neuronal differentiation in the piriform cortex.

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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.


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.


Cajal-Retzius neurons; Neurog1 and Neurog2; lateral olfactory tract guidepost cells; piriform cortex; proneural genes; ventral pallium

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