title: Regulation of differentiation flux by Notch signalling influences the number of dopaminergic neurons in the adult brain.
abstract: 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.
authors.affiliation: Departamento de Genética y Fisiología Molecular, Instituto de Biotecnología, Cuernavaca, Morelos 62210, México.
authors.forename: Niurka
authors.initials: N
authors.lastname: Trujillo-Paredes
authors.affiliation: Departamento de Genética y Fisiología Molecular, Instituto de Biotecnología, Cuernavaca, Morelos 62210, México.
authors.forename: Concepción
authors.initials: C
authors.lastname: Valencia
authors.affiliation: Departamento de Genética y Fisiología Molecular, Instituto de Biotecnología, Cuernavaca, Morelos 62210, México.
authors.forename: Gilda
authors.initials: G
authors.lastname: Guerrero-Flores
authors.affiliation: Departamento de Genética y Fisiología Molecular, Instituto de Biotecnología, Cuernavaca, Morelos 62210, México.
authors.forename: Dulce-María
authors.initials: DM
authors.lastname: Arzate
authors.affiliation: Departamento de Genética y Fisiología Molecular, Instituto de Biotecnología, Cuernavaca, Morelos 62210, México.
authors.forename: José-Manuel
authors.initials: JM
authors.lastname: Baizabal
authors.affiliation: Departamento de Neuropatología Molecular, Instituto de Fisiología Celular, Coyoacán, Ciudad de México 04510, México.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Guerra-Crespo
authors.affiliation: Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Morelos 62210, México.
authors.forename: Ayari
authors.initials: A
authors.lastname: Fuentes-Hernández
authors.affiliation: Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Morelos 62210, México.
authors.forename: Iván
authors.initials: I
authors.lastname: Zea-Armenta
authors.affiliation: Departamento de Genética y Fisiología Molecular, Instituto de Biotecnología, Cuernavaca, Morelos 62210, México covs@ibt.unam.mx.
authors.forename: Luis
authors.initials: L
authors.lastname: Covarrubias
keywords: Delta-like 1; Dopaminergic neurons; Neurogenesis; Notch