Regulation of differentiation flux by Notch signalling influences the number of dopaminergic neurons in the adult brain.

Niurka Trujillo-Paredes,Magdalena Guerra-Crespo,Concepción Valencia,Gilda Guerrero-Flores,Luis Covarrubias,Iván Zea-Armenta,José-Manuel Baizabal,Ayari Fuentes-Hernández,Dulce-María Arzate

doi:10.1242/bio.013383

Abstract

ABSTRACTNotch signalling is a well-established pathway that regulates neurogenesis. However, little is known about the role of Notch signalling in specific neuronal differentiation. Using Dll1 null mice, we found that Notch signalling has no function in the specification of mesencephalic dopaminergic neural precursor cells (NPCs), but plays an important role in regulating their expansion and differentiation into neurons. Premature neuronal differentiation was observed in mesencephalons of Dll1-deficient mice or after treatment with a Notch signalling inhibitor. Coupling between neurogenesis and dopaminergic differentiation was indicated from the coincident emergence of neuronal and dopaminergic markers. Early in differentiation, decreasing Notch signalling caused a reduction in NPCs and an increase in dopaminergic neurons in association with dynamic changes in the proportion of sequentially-linked dopaminergic NPCs (Msx1/2+, Ngn2+, Nurr1+). These effects in differentiation caused a significant reduction in the number of dopaminergic neurons produced. Accordingly, Dll1 haploinsufficient adult mice, in comparison with their wild-type littermates, have a consistent reduction in neuronal density that was particularly evident in the substantia nigra pars compacta. Our results are in agreement with a mathematical model based on a Dll1-mediated regulatory feedback loop between early progenitors and their dividing precursors that controls the emergence and number of dopaminergic neurons.

Highlights

At the cellular level, early embryogenesis involves stem and progenitor cell proliferation followed by their exit from the cell cycle and concurrent differentiation into specific cell types
Dll1 and Hes5 are key mediators of Notch signalling in the mesencephalic dopaminergic niche Dll1 transcript distribution in the developing mesencephalon has been previously determined by in situ hybridization; probably due to the quantitative limitations of this technique, the expression pattern has not been well defined showing scattered distribution with an apparent higher number of positive cells towards the subventricular area (Deng et al, 2011; Kele et al, 2006; Lahti et al, 2011)
Concluding remarks The initial specification of mesencephalic dopaminergic neural precursor cells (NPCs) occurs in the absence of Notch signalling

Summary

Introduction

Early embryogenesis involves stem and progenitor cell proliferation followed by their exit from the cell cycle and concurrent differentiation into specific cell types. Timing of cell differentiation may influence cell fate choice, given the fact that NSCs appear to change their potential over time throughout development It has been shown that specific cortical neurons arise at a different developmental time, suggesting that specification is associated with the time of birth (Okano and Temple, 2009; Shen et al, 2006). It is still unclear how cell differentiation timing influences cell fate choice and the histogenesis of specific brain regions

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Conclusion