Abstract
Sequential generation of neurons and glial cells during development is critical for the wiring and function of the cerebral cortex. This process requires accurate coordination of neural progenitor cell (NPC) fate decisions, by NPC-autonomous mechanisms as well as by negative feedback from neurons. Here, we show that neurogenesis is protracted and gliogenesis decreased in mice with mutations of genes Celsr3 and Fzd3. This phenotype is not due to gene inactivation in progenitors, but rather in immature cortical neurons. Mutant neurons are unable to upregulate expression of Jag1 in response to cortical Wnt7, resulting in blunted activation of Notch signalling in NPC. Thus, Celsr3 and Fzd3 enable immature neurons to respond to Wnt7, upregulate Jag1 and thereby facilitate feedback signals that tune the timing of NPC fate decisions via Notch activation.
Highlights
Sequential generation of neurons and glial cells during development is critical for the wiring and function of the cerebral cortex
Jak/Stat cytokines such as cardiotrophin-1 and CNTF produced by postmitotic neurons promote the production of glia[16,17,18], and neural progenitor cell (NPC) deficient in both Mek[1] and Mek[2] fail to switch from neurogenesis to gliogenesis due to attenuation of the cytokine-regulated gliogenic pathway[19]
Planar cell polarity (PCP) in epithelial sheets is regulated by various genes, among which the so called ‘core PCP’ genes include the seven pass transmembrane domain receptors Fzd[3] and 6, the atypical seven pass cadherins Celsr[1,2,3], the tetraspannins Vangl[1] and 2 and the adaptors Dishevelled (Dvl)[1,2,3] and Prickle[27,28]
Summary
Sequential generation of neurons and glial cells during development is critical for the wiring and function of the cerebral cortex. Notch[1,2,3,4] receptors on AP cells can be activated by ligands Delta (Dll1,3,4) or Jagged (Jag1, 2) on adjacent cells such as other AP located in ventricular zones or BP located in the subventricular zone[15] Those interactions play important roles in maintaining the AP population and inhibiting premature generation of neurons, which is not solely explained by regulation of differentiation timing[25]. Celsr[3] and Fzd[3] are required in immature neurons and possibly BP, to upregulate Jag[1] in response to Wnt[7], and to activate Notch signalling in AP, providing a feedback signal to tune AP cell fate and timing transitions
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