Oligodendrocytes (OGs) assemble the myelin sheath around axons in the central nervous system. Specification of cells into the OG lineage is largely the result of interplay between bone morphogenetic protein, sonic hedgehog and Notch signaling pathways, which regulate expression of transcription factors (TFs) dictating spatial and temporal aspects of oligodendrogenesis. Many of these TFs and others then direct OG development through to a mature myelinating OG. Here we describe signaling pathways and TFs that are inductive, inhibitory, and/or permissive to OG specification and maturation. We develop a basic transcriptional network and identify similarities and differences between regulation of oligodendrogenesis in the spinal cord and brain.

1. The olfactory epithelium (OE) is a simple structure that gives rise to olfactory sensory neurons (OSNs) throughout life. 2. Numerous transcription factors (TFs) are expressed in regions of the OE which contain progenitor cells and OSNs. The function of some of these TFs in OSN development has been elucidated with the aide of transgenic knockout mice. 3. We review here the current state of knowledge on the role of TFs in OE neurogenesis and relate the expression of these TFs, where possible, to the well-documented phenotype of the cells as they progress through the OSN lineage from progenitor cells to mature neurons.

Recent discoveries have enhanced our knowledge of the transcriptional control of oligodendrocyte (OG) development. In particular, the transcription factors (TFs) Olig2, Pax6, and Nkx2.2 have been shown to be important in the specification and/or maturation of the OG lineage. Although numerous other TFs are expressed by OGs, little is known regarding their role(s) in oligodendrogenesis. One such TF is the homeobox gene Hoxa2, which was recently shown to be expressed by O4(+) pro-oligodendrocytes. The objectives of this study were to examine the expression of Hoxa2 during the early stages of OG development, as well as to determine whether Hoxa2 is required for specification and/or early maturation of OGs. Immunocytochemical analysis of primary mixed glial cultures demonstrated that Hoxa2 was expressed throughout oligodendrogenesis, diminishing only with the acquisition of a myelinating phenotype. Serial transverse spinal cord sections from embryonic days 12.5, 14.25, 16, and 18 Hoxa2(+/+), Hoxa2(+/-), and Hoxa2(-/-) mice were subjected to single and double immunohistochemical analysis in order to examine Hoxa2, Olig2, Nkx2.2, and Pax6 expression profiles. Results obtained from Hoxa2(+/+) and Hoxa2(+/-) mice suggested that Hoxa2 was expressed by migratory oligodendroglial cells. In addition, comparison of spinal cord sections obtained from Hoxa2(+/+), Hoxa2(+/-), and Hoxa2(-/-) mice suggested that specification and early maturation of OGs proceeded normally in the absence of Hoxa2, since there were no obvious alterations in the expression patterns of Olig2, Nkx2.2, and/or Pax6. Hence, although Hoxa2 is expressed throughout OG development, it does not appear to be critical for early stages of oligodendrogenesis in the murine spinal cord.

(1) Little information exists on the role of clustered Hox genes in oligodendrocyte (OG) development. This study examines the expression profile of Hoxd1 and identifies a potential downstream target in the OG lineage. (2) Immunocytochemical analysis of primary mixed glial cultures demonstrated Hoxd1 was expressed throughout OG development. (3) A human myelin protein gene, myelin oligodendrocyte glycoprotein (MOG), was identified as a putative downstream target of Hoxdl through Genbank searches utilizing the Hoxdl homeodomain consensus binding sequence. (4) The dissociation coefficient constant (KD) and dissociation rate constant (kd) of the Hoxd1-MOG complex, determined using electrophoretic mobility shift assays (EMSAs), were estimated to be 1.9 x 10(-7) M and 1.3 x 10(-3) s(-1), respectively. The DNA-Hoxdl homeodomain complex had a half-life (t1/2) of 15 min. (5) Mutational analysis of Hoxd1-MOG complexes revealed the binding affinity of M1 (with mutation from (-1054)5'-TAAT-3'(-1051) to TACT within the consensus binding site) and M2 (with mutation from (-1054)5'-TAATTG-3'(-1049) to TAATCC within the consensus binding site) probes to the MOG promoter was severely affected. Thus the TAATTG core of the binding sequence appears important for Hoxd1 specificity. (6) Analysis of the involvement of TAAT sites adjacent to the consensus sequence in Hoxdl binding showed the binding affinity of the M3 probe was affected, but not as severely as the M1 and M2 probes. These in vitro results suggest the TTTAATTGTA sequence is involved in Hoxd1 binding to the MOG promoter but neighboring TAAT sites may also be needed. Thus, MOG may be a target of Hoxd1.

1. Although recent advances have provided insight into the transcriptional control of oligodendrocyte (OG) development, little information exists on the role of clustered Hox genes in this process. The aim of this study was to examine the expression profile of Hoxb4 in the oligodendroglial lineage. 2. Immunocytochemical analysis of primary mixed glial cultures demonstrated that Hoxb4 was expressed throughout OG development, being coexpressed with oligodendroglial markers, A2B5, O4 (97%). GalC (91%), and MBP (93%). 3. Immunohistochemical analysis of transverse spinal cord sections demonstrated diffuse expression of Hoxb4 throughout the spinal cord at E12.5 (C16/T19), after which expression was confined primarily to the presumptive gray matter. 4. At E14.25 (C19+/T21), Olig2+ cells had begun to migrate out from the ventral ventricular zone into the presumptive gray matter. These results suggest that Olig2+ cells could coexpress Hoxb4 since it is expressed throughout this region. 5. The expression of Hoxb4 by cells of the OG lineage indicates that it could play a role in OG maturation.