**5. Conclusions**

transducer and activator of transcription (STAT) binding elements. With this, astrocyte-spe‐ cific genes are transcriptionally activated through the Janus kinase (JAK)-STAT pathway, one of whose ligands is the cytokine leukemia inhibitory factor (LIF). However, neurogenic NPCs are not competent to differentiate into astrocytes even when they are grown with LIF, because the STAT-binding elements within astrocyte-specific genes promoters are methylat‐ ed [100, 101]. This DNA methylation inhibits the association of activated STATs with the promoter of astrocyte-specific genes, thereby repressing their transcription. Conditional de‐ letion of *DNMT1* in embryonic NPCs results in DNA hypomethylation and alteration of the timing of astrocytogenesis [101]. In addition, knockdown of *DNMT3B* in ESCs alters the tim‐ ing of their neural differentiation [102]. These findings suggest that DNA methylation con‐ trols the timing and developmental switch from neurogenesis to astrogliogenesis of NPCs

As NPCs exit the cell cycle and differentiate into mature neurons, BAF60C is incorporated into the npBAF complexes [80, 103]. BAF45A and BAF53A in the complexes give way to BAF45B/C and BAF53B, respectively (Figure 2) [80, 103], establishing the post-mitotic neu‐ ron-specific nBAF complexes. Preventing the exchange of npBAF and nBAF components im‐ pairs neuronal differentiation, indicating that a switch in subunit composition of the BAF complexes is required for the transition from pluripotent ESCs to post-mitotic neurons [80, 103]. The nBAF complexes, along with Ca2+-responsive dendritic regulator CREST, also play a role in regulating the activation of genes essential for activity-dependent dendritic out‐ growth, suggesting that the nBAF complexes are required for morphological/synaptic devel‐

The BAF complexes incorporate the BAF57 subunit containing DNA-binding HMG-box do‐ mains [105]. In addition, the BAF complex subunits contain motifs known to bind to modi‐ fied histones, including chromo-, bromo-, and PHD domains [103]. The bromodomain can bind acetylated histones [106]. The chromo- and PHD domains function as lysine-methylat‐ ed histone-binding domains [106]. The esBAF and npBAF complexes contain different chro‐ modomain proteins (BAF155 or BAF170) [103], whereas the npBAF and nBAF complexes contain different PHD domain proteins (BAF45a or BAF45b) [80, 103]. Thus, changes in sub‐ unit composition could alter targets of the BAF complexes, thereby causing changes in gene

A number of miRNAs involved in cell fate decision during stem cell differentiation is also highly expressed in the nervous systems. Among these is miR-9, which is expressed specifi‐ cally in neurogenic areas of the embryonic and adult brains [107, 108]. TLX, an orphan nu‐ clear receptor, is essential for maintaining a self-renewable and undifferentiated state [109], as well as cell cycle progression [110] of NPCs in the developing brain. TLX is highly ex‐ pressed in NPCs, but its expression is down-regulated upon neural differentiation [111]. Conversely, miR-9 expression increases during neural differentiation [111]. Furthermore,

by altering responsiveness to their extracellular developmental cues.

**4.3. Chromatin remodeling**

314 Trends in Cell Signaling Pathways in Neuronal Fate Decision

opment of neurons [103, 104].

**4.4. Non-coding RNAs**

expression patterns during neuronal differentiation.

Epigenetic mechanisms are regulatory processes that control gene expression via changes in chromatin structure without alterations in the DNA sequence. Changes in chromatin struc‐ ture alter the accessibility of transcription factors and RNA polymerase to genes packed into chromatin, thereby modulating the efficiency of gene transcription. Epigenetic mechanisms act to control this accessibility through histone modifications, DNA methylation, chromatin remodeling, and non-coding RNAs. Each of these epigenetic events interacts with intrinsic (ex. transcription factors) and/or extrinsic factors (ex. developmental cues such as morpho‐ gens and cytokines). Studies so far have suggested that, during sequential transitions from pluripotent ESCs to terminally differentiated neurons, epigenetic mechanisms play critical roles in not only maintaining self-renewal capacity and pluripotency of ESCs, but also re‐ stricting cell lineage choices. Further investigation will therefore help clarifying the mecha‐ nisms that control pluripotency and neuronal/glial fate specification. Furthermore, the knowledge will be used in harnessing ESCs safely and effectively for clinical applications.

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