Regulation of differentiation flux by Notch signalling influences the number of dopaminergic neurons in the adult brain
| Autor: | Iván Zea-Armenta, Luis Covarrubias, José-Manuel Baizabal, Niurka Trujillo-Paredes, Dulce-María Arzate, Magdalena Guerra-Crespo, Gilda Guerrero-Flores, Concepción Valencia, Ayari Fuentes-Hernandez |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Notch QH301-705.5 Neurogenesis Science Notch signaling pathway Substantia nigra Biology Delta-like 1 Bioinformatics Dopaminergic neurons General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Precursor cell Biology (General) Progenitor cell Pars compacta Dopaminergic Cell biology 030104 developmental biology nervous system General Agricultural and Biological Sciences Haploinsufficiency 030217 neurology & neurosurgery Research Article |
| Zdroj: | Biology Open, Vol 5, Iss 3, Pp 336-347 (2016) Biology Open |
| ISSN: | 2046-6390 |
| Popis: | Notch 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. Summary: The early emergence of dopaminergic neurons under reduced Notch signalling results from a change in the differentiation flux that defines the final number of neurons produced. |
| Databáze: | OpenAIRE |
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