PAK3 controls the tangential to radial migration switch of cortical interneurons by coordinating changes in cell shape and polarity

Abstract

<jats:title>SUMMARY</jats:title><jats:p>During the embryonic development, cortical interneurons migrate a long distance tangentially and then re-orient radially to settle in the cortical plate where they contribute to cortical circuits. Migrating interneurons express PAK3, a p21-activated kinase that switches between active and inactive states and controls interneuron migration by unknown mechanism(s). Here we examined the role of the kinase activity of PAK3 to regulate the migration of cortical interneurons. We showed that interneurons expressing a constitutively active PAK3 mutant (PAK3-ca) oriented preferentially radially in the cortex, extended short leading processes and exhibited unstable polarity. On the contrary, interneurons expressing an inactive PAK3 mutant (PAK3-kd for kinase dead) extended branched leading processes, showed directed nuclear movements and remained in the tangential pathways. Results showed that PAK3 kinase activity controls the switch between the tangential and radial modes of migration of cortical interneurons and identified myosin 2B as an effector of this switch.</jats:p>

CXCL12 targets the primary cilium cAMP/cGMP ratio to regulate cell polarity during migration

“…At any location along the tangential streams, a proportion of interneurons can re-orient radially in order to leave the tangential paths and to integrate the cortical plate (CP). This "tangential-to-radial switch" of migration represents a major directional change operated by migrating cortical interneurons to reach their cortical target 47 . Among the guidance cues required for cortical interneurons to migrate in the embryonic cortex, the CXCL12 chemokine secreted by the MZ and by cortical progenitors in the SVZ/IZ (intermediate zone), promotes the cortical interneuron tangential migration within the deep and superficial tangential migratory streams through binding to the CXCR7 and CXCR4 receptors 22,23,[48][49][50][51][52][53] .…”

Interneuron migration defects during corticogenesis contribute toDyrk1ahaploinsufficiency syndrome pathogenesis via actomyosin dynamics deregulations

“…More specifically, Dyrk1a controls the frequency of nucleokinesis and the amplitude of the forward progression of nuclei during these events, likely contributing to the net decrease of migration we observe in both mutants (Dyrk1a DlxCre/+ and Dyrk1a K188R/+ ). Abnormalities in INs development have been commonly associated with neurodevelopmental disorders 64 and lately several studies have demonstrated that migration defects contribute to the etiology of conditions like ID and ASD [65][66][67][68][69] . Reduced production of INs cell types and migration defects were also described in GABAergic neurons derived from DS iPSCs 61 , and proposed as being partly responsible for the reduced number of INs observed in DS brains.…”

CXCL12 targets the primary cilium cAMP/cGMP ratio to regulate cell polarity during migration

“…At any location along the tangential streams, a proportion of interneurons can reorient radially in order to leave the tangential paths and to integrate the cortical plate (CP). This "tangential-to-radial switch" of migration represents a major directional change operated by migrating cortical interneurons to reach their cortical target 48 . Among the guidance cues required for cortical interneurons to migrate in the embryonic cortex, the CXCL12 chemokine secreted by the MZ and by cortical progenitors in the SVZ/IZ (intermediate zone), promotes the cortical interneuron tangential migration within the deep and superficial tangential migratory streams through binding to the CXCR7 and CXCR4 receptors 22,23,[49][50][51] .…”