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Sacri R Ferrón,
Marika Charalambous,
Elizabeth Radford,
Kirsten McEwen,
Hendrik Wildner,
Eleanor Hind,
Jose Manuel Morante-Redolat,
Jorge Laborda, Francois Guillemot,
Steven R Bauer,
Isabel Fariñas,
Anne C Ferguson-Smith
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ABSTRACT: The gene for the atypical NOTCH ligand delta-like homologue 1 (Dlk1) encodes membrane-bound and secreted isoforms that function in several developmental processes in vitro and in vivo. Dlk1, a member of a cluster of imprinted genes, is expressed from the paternally inherited chromosome. Here we show that mice that are deficient in Dlk1 have defects in postnatal neurogenesis in the subventricular zone: a developmental continuum that results in depletion of mature neurons in the olfactory bulb. We show that DLK1 is secreted by niche astrocytes, whereas its membrane-bound isoform is present in neural stem cells (NSCs) and is required for the inductive effect of secreted DLK1 on self-renewal. Notably, we find that there is a requirement for Dlk1 to be expressed from both maternally and paternally inherited chromosomes. Selective absence of Dlk1 imprinting in both NSCs and niche astrocytes is associated with postnatal acquisition of DNA methylation at the germ-line-derived imprinting control region. The results emphasize molecular relationships between NSCs and the niche astrocyte cells of the microenvironment, identifying a signalling system encoded by a single gene that functions coordinately in both cell types. The modulation of genomic imprinting in a stem-cell environment adds a new level of epigenetic regulation to the establishment and maintenance of the niche, raising wider questions about the adaptability, function and evolution of imprinting in specific developmental contexts.
Nature 07/2011; 475(7356):381-5. · 36.28 Impact Factor
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ABSTRACT: dILA and dILB neurons comprise the major neuronal subtypes generated in the dorsal spinal cord, and arise in a salt-and-pepper pattern from a broad progenitor domain that expresses the bHLH factor Mash1. In this domain, Mash1-positive and Mash1-negative cells intermingle. Using a Mash1(GFP) allele in mice, we show here that Mash1+ progenitors give rise to dILA and dILB neurons. Using retroviral tracing in the chick, we demonstrate that a single progenitor can give rise to a dILA and a dILB neuron, and that dILA neurons are the product of asymmetric progenitor cell divisions. In Mash1-null mutant mice, the development of dILA, but not of dILB neurons is impaired. We provide evidence that a dual function of Mash1 in neuronal differentiation and specification accounts for the observed changes in the mutant mice. Our data allow us to assign to Mash1 a function in asymmetric cell divisions, and indicate that the factor coordinates cell cycle exit and specification in the one daughter that gives rise to a dILA neuron.
Development 07/2006; 133(11):2105-13. · 6.60 Impact Factor
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ABSTRACT: The dorsal spinal cord contains a diverse array of neurons that connect sensory input from the periphery to spinal cord motoneurons and brain. During development, six dorsal neuronal populations (dI1-dI6) have been defined by expression of homeodomain factors and position in the dorsoventral axis. The bHLH transcription factors Mash1 and Ngn2 have distinct roles in specification of these neurons. Mash1 is necessary and sufficient for generation of most dI3 and all dI5 neurons. Unexpectedly, dI4 neurons are derived from cells expressing low levels or no Mash1, and this population increases in the Mash1 mutant. Ngn2 is not required for any specific neuronal cell type but appears to modulate the composition of neurons that form. In the absence of Ngn2, there is an increase in the number of dI3 and dI5 neurons, in contrast to the effects produced by activity of Mash1. Mash1 is epistatic to Ngn2, and, unlike the relationship between other neural bHLH factors, cross-repression of expression is not detected. Thus, bHLH factors, particularly Mash1 and related family members Math1 and Ngn1, provide a code for generating neuronal diversity in the dorsal spinal cord with Ngn2 serving to modulate the number of neurons in each population formed.
Development 07/2005; 132(12):2709-19. · 6.60 Impact Factor
