Regulated expression of ATF5 is required for the progression of neural progenitor cells to neurons.
An important milestone in brain development is the transition of neuroprogenitor cells to postmitotic neurons. We report that the bZIP transcription factor ATF5 plays a major regulatory role in this process. In developing brain ATF5 expression is high within ventricular zones containing neural stem and progenitor cells and is undetectable in postmitotic neurons. In attached clonal neurosphere cultures ATF5 is expressed by neural stem/progenitor cells and is undetectable in tau-positive neurons. In PC12 cell cultures nerve growth factor (NGF) dramatically downregulates endogenous ATF5 protein and transcripts, whereas exogenous ATF5 suppresses NGF-promoted neurite outgrowth. Such inhibition requires the repression of CRE sites. In contrast, loss of function conferred by dominant-negative ATF5 accelerates NGF-promoted neuritogenesis. Exogenous ATF5 also suppresses, and dominant-negative ATF5 and a small-interfering RNA targeted to ATF5 promote, neurogenesis by cultured nestin-positive telencephalic cells. These findings indicate that ATF5 blocks the differentiation of neuroprogenitor cells into neurons and must be downregulated to permit this process to occur.
Angelastro
James M
JM
Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. jma14@columbia.edu
Ignatova
Tatyana N
TN
Kukekov
Valery G
VG
Steindler
Dennis A
DA
Stengren
George B
GB
Mendelsohn
Cathy
C
Greene
Lloyd A
LA
D051696:Activating Transcription Factors; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000196:embryology / Q000378:metabolism; D002999:Clone Cells; D015536:Down-Regulation / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005799:Genes, Dominant; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology*; D016716:PC12 Cells; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013687:Telencephalon / Q000166:cytology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology
D051696:Activating Transcription Factors; C471855:Atf5 protein, mouse; D015415:Biomarkers; D034741:RNA, Small Interfering; D014157:Transcription Factors; D020932:Nerve Growth Factor