title: Modification of pax6 and olig2 expression in adult hippocampal neurogenesis selectively induces stem cell fate and alters both neuronal and glial populations.
abstract: The generation of new neurons in the mammalian hippocampus continues throughout life, and lineage progression is regulated by transcription factors, local cues, and environmental influences. The ability to direct stem/progenitor cell fate in situ may have therapeutic potential. Using an in vivo retroviral delivery and lineage tracing approach, we compare the lineage-instruction factors, Pax6 and Olig2, and demonstrate that both participate in regulation of adult hippocampal neurogenesis in adult rats. We show that overexpression of the proneuronal factor Pax6 pushes neuronal precursor cells to early maturation and increases the frequency of neuronal phenotypes. However, Pax6 overexpression results in no net increase in neurogenesis at 3 weeks. Blocking of Olig2 function reduces and slows neuronal commitment and differentiation and decreases net neurogenesis. Altering expression of both factors also changes gliogenesis. Our results establish that Pax6 decreases the number of Neuron-Glia 2 progenitor cells and prevents oligodendrocytic lineage commitment, while repression of Olig2 results in an expanded astrocytic lineage. We conclude that selectively modifying transcriptional cues within hippocampal progenitor cells is sufficient to induce a cell fate switch, thus altering the neurogenesis-gliogenesis ratio. In addition, our data show the competence of multiple progenitor lineages to respond divergently to the same signal. Therefore, directing instructive cues to select phenotype and developmental stage could be critical to achieve precise outcomes in cell genesis. Further understanding the regulation of lineage progression in all progenitor populations within the target region will be important for developing therapeutic strategies to direct cell fate for brain repair.
authors.affiliation: Department of Neuroscience, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors.forename: Friederike
authors.initials: F
authors.lastname: Klempin
authors.forename: Robert A
authors.initials: RA
authors.lastname: Marr
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Peterson
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage; D049109:Cell Proliferation; D048430:Cell Shape; D002470:Cell Survival; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology; D055495:Neurogenesis; D009457:Neuroglia / Q000166:cytology* / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D044968:Regenerative Medicine; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000943:Antigens, Differentiation; D051792:Basic Helix-Loop-Helix Proteins; D005136:Eye Proteins; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D011994:Recombinant Proteins; D012097:Repressor Proteins; C522729:Olig2 protein, rat; C000605733:Pax6 protein, rat