Drosha regulates neurogenesis by controlling neurogenin 2 expression independent of microRNAs.
Temporal regulation of embryonic neurogenesis is controlled by hypostable transcription factors. The mechanism of the process is unclear. Here we show that the RNase III Drosha and DGCR8 (also known as Pasha), key components of the microRNA (miRNA) microprocessor, have important functions in mouse neurogenesis. Loss of microprocessor in forebrain neural progenitors resulted in a loss of stem cell character and precocious differentiation whereas Dicer deficiency did not. Drosha negatively regulated expression of the transcription factors Neurogenin 2 (Ngn2) and NeuroD1 whereas forced Ngn2 expression phenocopied the loss of Drosha. Neurog2 mRNA contains evolutionarily conserved hairpins with similarities to pri-miRNAs, and associates with the microprocessor in neural progenitors. We uncovered a Drosha-dependent destabilization of Neurog2 mRNAs consistent with microprocessor cleavage at hairpins. Our findings implicate direct and miRNA-independent destabilization of proneural mRNAs by the microprocessor, which facilitates neural stem cell (NSC) maintenance by blocking accumulation of differentiation and determination factors.
Department of Molecular Embryology, Max Planck Institute of Immunology, Freiburg, Germany.
Philip
P
Knuckles
Miriam A
MA
Vogt
Sebastian
S
Lugert
Marta
M
Milo
Mark M W
MM
Chong
Guillaume M
GM
Hautbergue
Stuart A
SA
Wilson
Dan R
DR
Littman
Verdon
V
Taylor
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy; D043244:Ribonuclease III / Q000037:antagonists & inhibitors / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D043244:Ribonuclease III; C102938:Neurog2 protein, mouse; C513400:Drosha protein, mouse