UNDERSTANDING THE ROLE OF CTCF IN MOUSE NEURAL PRECURSOR CELLS

CCCTC-binding factor (CTCF) is a key regulator of chromatin organization. Recent studies indicate that Ctcf is essential for proper mouse development. CTCF depletion in mouse oocyte results in embryo death, while CTCF heterozygous mice develop tumors. CTCF expression changes during brain development. Inactivation of CTCF in mouse neural precursor (NP) cells can lead to premature neurogenesis. The mechanisms of this phenomenon are not fully defined. We found that in the mouse NP cells, acute removal of CTCF in vitro, upregulated expression of pro-neuronal genes including Tubb3, Ngfr, Lrrk2, Nrp1, Insm1, Dlx1, Dlx2 while downregulating Sox9, Sox5, Hes5 which are important for astrocytic fate. To determine how CTCF may impact further development of the NP cells we grew the NP cells in conditions promoting either neuronal and astrocytic identity. Neuronal differentiation and maturation of NP cells was enhanced when CTCF was abolished. On the contrary, the CTCF – NP cells yielded two times less astrocytes as judged by the expression of Gfap+ (35% versus 75% of Gfap+ cells in the CTCF+ population). Our results suggest that CTCF molds the differentiation trajectory in mouse NP cells. We are currently investigating the mechanisms by which CTCF impacts proneural and astrocytic gene expression. We are particularly interested in the molecular pathways that render some loci receptive to the level of CTCF. Likewise, we would like to determine how CTCF impacts NP cell biology and how its functions may be related to the development of neurological syndromes in patients with heterozygous deletion of the CTCF gene.