Regulated segregation of kinase Dyrk1A during asymmetric neural stem cell division is critical for EGFR-mediated biased signaling.
Stem cell division can result in two sibling cells exhibiting differential mitogenic and self-renewing potential. Here, we present evidence that the dual-specificity kinase Dyrk1A is part of a molecular pathway involved in the regulation of biased epidermal growth factor receptor (EGFR) signaling in the progeny of dividing neural stem cells (NSC) of the adult subependymal zone (SEZ). We show that EGFR asymmetry requires regulated sorting and that a normal Dyrk1a dosage is required to sustain EGFR in the two daughters of a symmetrically dividing progenitor. Dyrk1A is symmetrically or asymmetrically distributed during mitosis, and biochemical analyses indicate that it prevents endocytosis-mediated degradation of EGFR by a mechanism that requires phosphorylation of the EGFR signaling modulator Sprouty2. Finally, Dyrk1a heterozygous NSCs exhibit defects in self-renewal, EGF-dependent cell-fate decisions, and long-term persistence in vivo, suggesting that symmetrical divisions play a role in the maintenance of the SEZ reservoir.
Ferron
Sacri R
SR
Departamento de Biología Celular and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universidad de Valencia, 46100 Burjassot, Spain.
Pozo
Natividad
N
Laguna
Ariadna
A
Aranda
Sergi
S
Porlan
Eva
E
Moreno
Mireia
M
Fillat
Cristina
C
de la Luna
Susana
S
Sánchez
Pilar
P
Arbonés
María L
ML
Fariñas
Isabel
I
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002455:Cell Division; D002465:Cell Movement; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008938:Mitosis; D058953:Neural Stem Cells / Q000166:cytology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D055550:Protein Stability; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction; D000097603:Dyrk Kinases
D048868:Adaptor Proteins, Signal Transducing; D066246:ErbB Receptors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C118389:Spry2 protein, mouse