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Methyl-CpG-binding domain 1 (MBD1) belongs to a family of methyl-CpG-binding proteins that are epigenetic "readers" linking DNA methylation to transcriptional regulation. MBD1 is expressed in neural stem cells residing in the dentate gyrus of the adult hippocampus (aNSCs) and MBD1 deficiency leads to reduced neuronal differentiation, impaired neurogenesis, learning deficits, and autism-like behaviors in mice; however, the precise function of MBD1 in aNSCs remains unexplored. Here, we show that MBD1 is important for maintaining the integrity and stemness of NSCs, which is critical for their ability to generate neurons. MBD1 deficiency leads to the accumulation of undifferentiated NSCs and impaired transition into the neuronal lineage. Transcriptome analysis of neural stem and progenitor cells isolated directly from the dentate gyrus of MBD1 mutant (KO) and WT mice showed that gene sets related to cell differentiation, particularly astrocyte lineage genes, were upregulated in KO cells. We further demonstrated that, in NSCs, MBD1 binds and represses directly specific genes associated with differentiation. Our results suggest that MBD1 maintains the multipotency of NSCs by restraining the onset of differentiation genes and that untimely expression of these genes in MBD1-deficient stem cells may interfere with normal cell lineage commitment and cause the accumulation of undifferentiated cells. Our data reveal a novel role forMBD1in stem cell maintenance and provide insight into how epigenetic regulation contributes to adult neurogenesis and the potential impact of its dysregulation. [ABSTRACT FROM AUTHOR]

The mammalian cerebellum consists of folds of different sizes and shapes that house distinct neural circuits. A crucial factor underlying foliation is the generation of granule cells (gcs), the most numerous neuron type in the brain. We used clonal analysis to uncover global as well as folium size-specific cellular behaviors that underlie cerebellar morphogenesis. Unlike most neural precursors, gc precursors divide symmetrically, accounting for their massive expansion. We found that oriented cell divisions underlie an overall anteroposteriorly polarized growth of the cerebellum and gc clone geometry. Clone geometry is further refined by mediolateral oriented migration and passive dispersion of differentiating gcs. Most strikingly, the base of each fissure acts as a boundary for gc precursor dispersion, which we propose allows each folium to be regulated as a developmental unit. Indeed, the geometry and size of clones in long and short folia are distinct. Moreover, in engrailed 1/2 mutants with shorter folia, clone cell number and geometry are most similar to clones in short folia of wild-type mice. Thus, the cerebellum has a modular mode of development that allows the plane of cell division and number of divisions to be differentially regulated to ensure that the appropriate number of cells are partitioned into each folium. [ABSTRACT FROM AUTHOR]

During animal development, tissues and organs are partitioned into compartments that do not intermix. This organizing principle is essential for correct tissue morphogenesis. Given that cell sorting defects during compartmentalization in humans are thought to cause malignant invasion and congenital defects such as cranio-fronto-nasal syndrome, identifying the molecular and cellular mechanisms that keep cells apart at boundaries between compartments is important. In both vertebrates and invertebrates, transcription factors and short-range signalling pathways, such as EPH/Ephrin, Hedgehog, or Notch signalling, govern compartmental cell sorting. However, the mechanisms that mediate cell sorting downstream of these factors have remained elusive for decades. Here, we review recent data gathered in Drosophila that suggest that the generation of cortical tensile forces at compartmental boundaries by the actomyosin cytoskeleton could be a general mechanism that inhibits cell mixing between compartments. [ABSTRACT FROM AUTHOR]

Abstract: Considerable progress is being achieved in the analysis of gene regulatory networks that direct cell fate decisions within the hematopoietic system. In addition to transcription factors that are pivotal for cell fate specification and commitment, recent evidence suggests the involvement of microRNAs. In this review we attempt to integrate these two types of regulatory components into circuits that dictate cell fate choices leading to the generation of innate as well as adaptive immune cells. The developmental circuits are placed in the context of a revised scheme for hematopoiesis that suggests that both the innate (myeloid) and adaptive (lymphoid) lineages of the immune system arise from a common progenitor. [Copyright &y& Elsevier]

Abstract: Pbx proteins are a family of TALE-class transcription factors that are well characterized as Hox co-factors acting to impart segmental identity to the hindbrain rhombomeres. However, no role for Pbx in establishing more anterior neural compartments has been demonstrated. Studies done in Drosophila show that Engrailed requires Exd (Pbx orthologue) for its biological activity. Here, we present evidence that zebrafish Pbx proteins cooperate with Engrailed to compartmentalize the midbrain by regulating the maintenance of the midbrain–hindbrain boundary (MHB) and the diencephalic–mesencephalic boundary (DMB). Embryos lacking Pbx function correctly initiate midbrain patterning, but fail to maintain eng2a, pax2a, fgf8, gbx2, and wnt1 expression at the MHB. Formation of the DMB is also defective as shown by a caudal expansion of diencephalic epha4a and pax6a expression into midbrain territory. These phenotypes are similar to the phenotype of an Engrailed loss-of-function embryo, supporting the hypothesis that Pbx and Engrailed act together on a common genetic pathway. Consistent with this model, we demonstrate that zebrafish Engrailed and Pbx interact in vitro and that this interaction is required for both the eng2a overexpression phenotype and Engrailed''s role in patterning the MHB. Our data support a novel model of midbrain development in which Pbx and Engrailed proteins cooperatively pattern the mesencephalic region of the neural tube. [Copyright &y& Elsevier]

Abstract: DNA methylation-dependent gene silencing, mediated by DNA methyltransferases (DNMTs), is essential for normal mammalian development and its dysregulation has been implicated in neurodevelopmental disorders. Despite this, little is known about DNMTs in the developing or mature nervous system. Here, we show that DNMT1, 3a and 3b are expressed at discrete developmental stages in the olfactory neuron lineage, coincident with key shifts in developmental gene expression. DNMT1 is induced in cycling progenitors and is retained in post-mitotic olfactory receptor neurons (ORNs). DNMT3b is restricted to mitotic olfactory progenitors, whereas DNMT3a is expressed only in post-mitotic immature neurons prior to ORN terminal maturation, coincident with histone deacetylase 2 (HDAC2), a key downstream effector of methylation-dependent chromatin condensation. Similar stage-specific expression of DNMT3b and 3a was also found in other developing sensory and CNS neurons. This suggests that progressive lineage restriction regulated by methylation-dependent silencing could be a highly conserved mechanism shared by multiple lineages in the developing nervous system. [Copyright &y& Elsevier]

The vertebrate hindbrain is subdivided into segments, termed neuromeres, that are units of gone expression, cell differentiation and behavior. A key property of such segments is that cells show a restricted ability to mix across segment borders--termed lineage restriction. In order to address segmentation in the midbrain-hindbrain boundary (mhb) region, we have analyzed single cell behavior in the living embryo by acquiring time-lapse movies of the developing mhb region in a transgenic zebrafish line. We traced the movement of hundreds of nuclei, and by matching their position with the expression of a midbrain marker, we demonstrate that midbrain and hindbrain cells arise from two distinct cell populations. Single cell labeling and analysis of the distribution of their progeny shows that lineage restriction is probably established during late gastrulation stages. Our findings suggest that segmentation as an organizing principle in early brain development can be extended to the mhb region. We argue that lineage restriction serves to constrain the position of the mhb organizer cell population. [ABSTRACT FROM AUTHOR]

Summary Progenitor cells differentiate into specialized cell types through coordinated expression of lineage-specific genes and modification of complex chromatin configurations. We demonstrate that a histone deacetylase (Hdac3) organizes heterochromatin at the nuclear lamina during cardiac progenitor lineage restriction. Specification of cardiomyocytes is associated with reorganization of peripheral heterochromatin, and independent of deacetylase activity, Hdac3 tethers peripheral heterochromatin containing lineage-relevant genes to the nuclear lamina. Deletion of Hdac3 in cardiac progenitor cells releases genomic regions from the nuclear periphery, leading to precocious cardiac gene expression and differentiation into cardiomyocytes; in contrast, restricting Hdac3 to the nuclear periphery rescues myogenesis in progenitors otherwise lacking Hdac3. Our results suggest that availability of genomic regions for activation by lineage-specific factors is regulated in part through dynamic chromatin-nuclear lamina interactions and that competence of a progenitor cell to respond to differentiation signals may depend upon coordinated movement of responding gene loci away from the nuclear periphery. [ABSTRACT FROM AUTHOR]

Relatively little is known about the development of the thalamus, especially its differentiation into distinct nuclei. We demonstrate here that Gbx2-expressing cells in mouse diencephalon contribute to the entire thalamic nuclear complex. However, the neuronal precursors for different thalamic nuclei display temporally distinct Gbx2 expression patterns. Gbx2-expressing cells and their descendents form sharp lineage-restriction boundaries delineating the thalamus from the pretectum, epithalamus and prethalamus, revealing multiple compartmental boundaries within the mouse diencephalon. Without Gbx2, cells originating from the thalamus abnormally contribute to the epithalamus and pretectum. This abnormality does not result from an overt defect in patterning or cell-fate specification in Gbx2 mutants. Chimeric and genetic mosaic analysis demonstrate that Gbx2 plays a cell-nonautonomous role in controlling segregation of postmitotic thalamic neurons from the neighboring brain structures that do not express Gbx2. We propose that, within the developing thalamus, the dynamic and differential expression of Gbx2 may be involved in the specific segregation of thalamic neurons, leading to partition of the thalamus into different nuclei. [ABSTRACT FROM AUTHOR]