The Role Of PP2A In Cortical Development

Mammalian cortical development processes are governed by various regulatory mechanisms including signaling transduction pathways employing reversible phosphorylation and dephosphorylation.It is well established that the process of brain development involves many protein kinases,which regulate protein phosphorylation,whereas much less is known about the involvement of phosphatases,which regulate protein dephosphorylation,in the process.Since phosphatases generally have broader substrate specificity and more diverse cellular function than protein kinases,the role of phosphatase in cortical development should be much more complex,and a better understanding of it shall bring brighter insight into the regulatory mechanisms of cortical development.Recent studies on Protein phosphatase 4c(PP4c)c KO mice has proposed a potential mechanism for the involvement of protein phosphatases in corticogenesis,likely via Notch-dependent spindle orientation and proliferation of neuronal progenitor cell(NPCs).However,it remains unknown whether this mechanism is specifically utilized by PP4 c or could serve as a common one for protein phosphatases.Protein phosphatase 2A(PP2A)is a ubiquitously expressed phosphatase in the cell.As the principal member of the Ser/Thr phosphatase family,PP2 A is involved in many cellular processes including cell proliferation and differentiation,gene expression,neurotransmission and apoptosis.PP2 A is the major Ser/Thr phosphatase in the brain and has been found to be expressed in brain during embryonic and early postnatal stage.It has been reported that PP2 A is important for axonal and dendritic development,and loss-of-function mutations on PP2 A have been detected in neurodevelopmental diseases.However,mechanisms by which PP2 A regulates cortical development are unknown.To address this question,we conditionally inactivate the catalytic subunit-? of PP2A(PP2Ac?)in neural progenitor cells(NPCs)in the dorsal telencephalon of mice.The deletion of PP2Ac? in NPCs causes microcephaly and deficient cortical lamination of the superficial cortical layers.We illustrated that the defective cortical lamination may be resulted from the deficit migration of later-born neurons.Interestingly,the PP2Ac?inactivation has no significant effect on the proliferation and cell cycle re-entry of NPCs,but causes dislocation of the cell bodies of radial glial progenitors(RGPs).Normal RGPs mostly stay in the telencephalic stem cell niche in the ventricular zoom(VZ)during cortical development,but with the loss of PP2Ac? many of the RGPs can be observed outside of the VZ.To evaluate the effect of the dislocation of RGPs to cortical development,we investigate the proliferative capacity of the dislocated RGPs and find no remarkable difference with the normally located RGPs.Normal RGPs undergo mitosis at the apical surface of the VZ and the divisions may result in the expansion of RGP population or the generation of other types of neuronal cells.However,the mitosis of dislocated RGPs take place in cortical areas outside of the VZ,and they cannot increase the population RGPs.Finally,the cortical size and layer formation are disrupted by the impaired RGPs.To further study how PP2Ac? associate with the retention of RGPs in the telencephalic niche,we examine the adherens junctions in the apical surface of the VZ,as PP2 A expressed abundantly at apical surface,and adhesion mediated by apical adherens junctions is crucial for the positioning and apical migration of the RGPs.We discover that PP2Ac? deletion disrupts apical adherens junctions.Furthermore,we confirm the molecular interactions between PP2Ac? and components of apical adherens junctions,including N-cadherin and ?-catenin.In conclusion,these findings highlight the importance of PP2 A during cortical development and support the causal role of PP2 A loss-of-function mutations in cortical developmental diseases.Moreover,this study uncovers an essential role of PP2 A in the retention of RGPs in the niche during cortical development.