Temporal expression of neuronal connexins during hippocampal ontogeny

• Published in: Brain Research Reviews 2000-04, Vol.32 (1), p.57-71
• Main Authors: Rozental, R., Srinivas, M., Gökhan, S., Urban, M., Dermietzel, R., Kessler, J.A., Spray, D.C., Mehler, M.F.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; connexin 36; Cx26; Cx33; Cx36; Cx37; Cx40; Cx43; Cx45; Development. Senescence. Regeneration. Transplantation; Electrotonic synapse; Fundamental and applied biological sciences. Psychology; Gap junction; Hippocampus; ion channels (ligand-gated); Membrane channels (ligand-gated); nestin; neuroepithelial cells; neuroepithelium; Neuronal differentiation; Rodentia; RT–PCR; Vertebrates: nervous system and sense organs
• ISSN: 0165-0173; 1872-6321
• DOI: 10.1016/S0165-0173(99)00096-X

Communication through gap junction channels provides a major signaling mechanism during early brain histogenesis, a developmental time during which neural progenitor cells are inexcitable and do not express ligand-gated channel responses to the major CNS neurotransmitters. Expression of different gap junction types during neurogenesis may therefore define intercellular pathways for transmission of developmentally relevant molecules. To better understand the molecular mechanism(s) by which growth and differentiation of neurons are modulated by gap junction channels, we have been examining the developmental effects of a specific set of cytokines on differentiation and gap junction expression in a conditionally immortalized mouse embryonic hippocampal neuronal progenitor cell line (MK31). When multipotent MK31 cells are in an uncommitted state, they uniformly express the neuroepithelial intermediate filament class VI marker, nestin, are strongly coupled by gap junctions composed of connexin43 (Cx43) and express connexin45 (Cx45) at the mRNA level. As these cells undergo neuronal lineage commitment and exit from cell cycle, they begin to express the early neurofilament marker, NF66, and coupling strength and expression of Cx43 begin to decline with concurrent expression of other connexin proteins, including Cx26, Cx33, Cx36, Cx40 and Cx45. Terminal neuronal differentiation is heralded by the expression of more advanced neurofilament proteins, increased morphologic maturation, the elaboration of inward currents and action potentials that possess mature physiological properties, and changing profiles of expression of connexin subtypes, including upregulation of Cx36 expression. These important developmental transitions are regulated by a complex network of cell cycle checkpoints. To begin to examine the precise roles of gap junction proteins in traversing these developmental checkpoints and in thus regulating neurogenesis, we have focused on individual members of two classes of genes involved in these seminal events: ID (inhibitor of differentiation)-1 and GAS (growth arrest-specific gene)5. When MK31 cells were maintained in an uncommitted state, levels of ID-1 mRNA were high and GAS5 transcripts were essentially undetectable. Application of cytokines that promote neuronal lineage commitment and cell cycle exit resulted in down-regulation of ID-1 and upregulation of GAS5 transcripts, whereas additional cytokine paradigms that promoted terminal neuronal differen