Restriction of Neural Precursor Ability to Respond to Nurr1 by Early Regional Specification

Chiara Soldati,Isabella Saggio,Giuseppe Lupo,Carla Perrone-Capano,Stefano Biagioni,Nicoletta Carucci,Emanuele Cacci,Gabriella Augusti-Tocco

doi:10.1371/journal.pone.0051798

Abstract

During neural development, spatially regulated expression of specific transcription factors is crucial for central nervous system (CNS) regionalization, generation of neural precursors (NPs) and subsequent differentiation of specific cell types within defined regions. A critical role in dopaminergic differentiation in the midbrain (MB) has been assigned to the transcription factor Nurr1. Nurr1 controls the expression of key genes involved in dopamine (DA) neurotransmission, e.g. tyrosine hydroxylase (TH) and the DA transporter (DAT), and promotes the dopaminergic phenotype in embryonic stem cells. We investigated whether cells derived from different areas of the mouse CNS could be directed to differentiate into dopaminergic neurons in vitro by forced expression of the transcription factor Nurr1. We show that Nurr1 overexpression can promote dopaminergic cell fate specification only in NPs obtained from E13.5 ganglionic eminence (GE) and MB, but not in NPs isolated from E13.5 cortex (CTX) and spinal cord (SC) or from the adult subventricular zone (SVZ). Confirming previous studies, we also show that Nurr1 overexpression can increase the generation of TH-positive neurons in mouse embryonic stem cells. These data show that Nurr1 ability to induce a dopaminergic phenotype becomes restricted during CNS development and is critically dependent on the region of NPs derivation. Our results suggest that the plasticity of NPs and their ability to activate a dopaminergic differentiation program in response to Nurr1 is regulated during early stages of neurogenesis, possibly through mechanisms controlling CNS regionalization.

Highlights

During development, lineage commitment is a multistep process requiring the activation and repression of sets of genes at successive stages, leading from an embryonic stem (ES) to a tissue-specific stem cell identity as neural stem cells (NSCs)
FoxG1 is expressed in the developing mouse telencephalon (CTX and ganglionic eminence (GE)), Dlx2 and Six3 are expressed in the developing GE, HoxB6 and HoxB9 are expressed in the developing spinal cord (SC), while Ngn2 is expressed in both CTX and SC [7,8,10,27,28,29,30]
These observations are consistent with a recent study showing that region-specific molecular signatures are preserved in neural precursors (NPs) derived from different areas of the developing mouse central nervous system (CNS) [10], indicating that positional identities are at least partially maintained by NPs used to test Nurr1 ability to promote dopaminergic cell fates

Summary

Introduction

Lineage commitment is a multistep process requiring the activation and repression of sets of genes at successive stages, leading from an embryonic stem (ES) to a tissue-specific stem cell identity as neural stem cells (NSCs). How and when the different phenotypic features that underlie cell diversity are specified is an important issue in developmental neuroscience. Despite major progresses in this field, the molecular mechanisms as well as the extrinsic and intrinsic factors underlying lineage commitment in NSCs remain only partially understood [3,4,5]. In this context, an important issue is to understand when positional identity is acquired by neural precursors (NPs) and whether it can be maintained when NPs are removed from their environment and cultured in vitro under defined experimental conditions

Methods

Results

Conclusion