Cortical and Clonal Contribution of Tbr2 Expressing Progenitors in the Developing Mouse Brain.

Navneet A Vasistha,Elizabeth J Robertson,Siddharth Arora,Amanda F.P Cheung,Zoltán Molnár,Sebastian J Arnold,Fernando García-Moreno

doi:10.1093/cercor/bhu125

Navneet A Vasistha, Elizabeth J Robertson + Show 5 more

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https://doi.org/10.1093/cercor/bhu125

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Abstract

The individual contribution of different progenitor subtypes towards the mature rodent cerebral cortex is not fully understood. Intermediate progenitor cells (IPCs) are key to understanding the regulation of neuronal number during cortical development and evolution, yet their exact contribution is much debated. Intermediate progenitors in the cortical subventricular zone are defined by expression of T-box brain-2 (Tbr2). In this study we demonstrate by using the Tbr2Cre mouse line and state-of-the-art cell lineage labeling techniques, that IPC derived cells contribute substantial proportions 67.5% of glutamatergic but not GABAergic or astrocytic cells to all cortical layers including the earliest generated subplate zone. We also describe the laminar dispersion of clonally derived cells from IPCs using a recently described clonal analysis tool (CLoNe) and show that pair-generated cells in different layers cluster closer (142.1 ± 76.8 μm) than unrelated cells (294.9 ± 105.4 μm). The clonal dispersion from individual Tbr2 positive intermediate progenitors contributes to increasing the cortical surface. Our study also describes extracortical contributions from Tbr2+ progenitors to the lateral olfactory tract and ventromedial hypothalamic nucleus.

Highlights

Intermediate progenitor cells (IPCs) are transient transitamplifying progenitors present during neocortical neurogenesis that arise by asymmetric divisions of radial glial progenitors (Haubensak et al 2004; Miyata et al 2004; Noctor et al 2004)
In contrast to other subventricular zone (SVZ) markers, such as the Cux2 gene, T-box brain-2 (Tbr2) is solely expressed in the IPCs while Cux2 expression can be seen in the upper cortical layers of the cerebral cortex and in some fate-restricted populations of radial glial cells (Zimmer et al 2004), (Franco et al 2012) thereby complicating its use as an IPC marker
We found that the Cre-recombinase is selectively expressed in the cortical proliferative zones but not in the thin cortical plate (CP) at this stage (Fig. 1A,A′)

Summary

Introduction

Intermediate progenitor cells (IPCs) are transient transitamplifying progenitors present during neocortical neurogenesis that arise by asymmetric divisions of radial glial progenitors (Haubensak et al 2004; Miyata et al 2004; Noctor et al 2004) These progenitors reside in the subventricular zone (SVZ) where the majority terminally divide to produce a pair of neurons (Noctor et al 2004). Previous fate-mapping using a Neurod (NEX) driven Cre mouse line has shown IPC contribution towards the formation of upper layers (Wu et al 2005) This is further supported by the large decrease in the upper cortical layer thickness and Cux1+ cells in Tbr conditionally deleted mice (Arnold et al 2008). With recent studies showing large numbers of IPCs in both these regions (Hansen et al 2010; Reillo et al 2010; Fietz and Huttner 2011; García-Moreno et al 2012), it suggests that IPCs could be involved in formation of infragranular layers, at least in larger brains

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