Downregulation of activating transcription factor 5 is required for differentiation of neural progenitor cells into astrocytes.
The mechanisms that regulate neural progenitor cell differentiation are primarily unknown. The transcription factor activating transcription factor 5 (ATF5) is expressed in neural progenitors of developing brain but is absent from mature astrocytes and neurons. Here, we demonstrate that ATF5 regulates the conversion of ventricular zone (VZ) and subventricular zone (SVZ) neural progenitors into astrocytes. Constitutive ATF5 expression maintains neural progenitor cell proliferation and blocks their in vitro and in vivo differentiation into astrocytes. Conversely, loss of ATF5 function promotes cell-cycle exit and allows astrocytic differentiation in vitro and in vivo. CNTF, a promoter of astrocytic differentiation, downregulates endogenous ATF5, whereas constitutively expressed ATF5 suppresses CNTF-promoted astrocyte genesis. Unexpectedly, constitutive ATF5 expression in neonatal SVZ cells both in vitro and in vivo causes them to acquire properties and anatomic distributions of VZ cells. These findings identify ATF5 as a key regulator of astrocyte formation and potentially of the VZ to SVZ transition.
Angelastro
James M
JM
Department of Pathology and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. jmangelastro@ucdavis.edu
Mason
Jeffrey L
JL
Ignatova
Tatyana N
TN
Kukekov
Valery G
VG
Stengren
George B
GB
Goldman
James E
JE
Greene
Lloyd A
LA
D051696:Activating Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004622:Embryo, Mammalian; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D007150:Immunohistochemistry / Q000379:methods; D007381:Intermediate Filament Proteins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D018613:Microscopy, Confocal / Q000379:methods; D008953:Models, Anatomic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D039842:Neural Cell Adhesion Molecule L1 / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012794:Sialic Acids / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D014162:Transfection / Q000379:methods; D014404:Tubulin / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D051696:Activating Transcription Factors; D020934:Ciliary Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D039842:Neural Cell Adhesion Molecule L1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012794:Sialic Acids; D014404:Tubulin; D051176:beta Catenin; C103469:polysialyl neural cell adhesion molecule; D049452:Green Fluorescent Proteins; D001973:Bromodeoxyuridine