Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain.
Embryonic multipotent neural precursors are exposed to extracellular signals instructing them to adopt different fates, neuronal or glial. However, the mechanisms by which precursors integrate these signals to make timely fate choices remained undefined. Here we show that direct nuclear signaling by a receptor tyrosine kinase inhibits the responses of precursors to astrocyte differentiation factors while maintaining their neurogenic potential. Upon neuregulin-induced activation and presenilin-dependent cleavage of ErbB4, the receptor's intracellular domain forms a complex with TAB2 and the corepressor N-CoR. This complex undergoes nuclear translocation and binds promoters of astrocytic genes, repressing their expression. Consistent with this observation, astrogenesis occurs precociously in ErbB4 knockout mice. Our studies define how presenilin-dependent nuclear signaling by a receptor tyrosine kinase directly regulates gene transcription and cell fate. This pathway could be of importance for neural stem cell biology and for understanding the pathogenesis of Alzheimer's disease.
Sardi
S Pablo
SP
Neurobiology Program and Department of Neurology, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.
Murtie
Joshua
J
Koirala
Samir
S
Patten
Brooke A
BA
Corfas
Gabriel
G
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000196:embryology; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D020890:Neuregulin-1 / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D053763:Presenilins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D051381:Rats; D066247:Receptor, ErbB-4; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; C539127:NCOR1 protein, human; C539128:Ncor1 protein, mouse; C539129:Ncor1 protein, rat; D020890:Neuregulin-1; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D053763:Presenilins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C410585:TAB2 protein, human; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4