Elongator controls cortical interneuron migration by regulating actomyosin dynamics (original) (raw)
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Journal of Neuroscience, 2010
Neuronal migration is a complex process requiring the coordinated interaction of cytoskeletal components and regulated by calcium signaling among other factors. Migratory neurons are polarized cells in which the largest intracellular organelle, the nucleus, has to move repeatedly. Current views support a central role for pulling forces that drive nuclear movement. The participation of actomyosin driven forces acting at the nucleus rear has been suggested, however its precise contribution has not been directly addressed. By analyzing interneurons migrating in cortical slices of mouse brains, we have found that nucleokinesis is associated with a precise pattern of actin dynamics characterized by the initial formation of a cup-like actin structure at the rear nuclear pole. Time-lapse experiments show that progressive actomyosin contraction drives the nucleus forward. Nucleokinesis concludes with the complete contraction of the cup-like structure, resulting in an actin spot at the base of the retracting trailing process. Our results demonstrate that this actin remodeling requires a threshold calcium level provided by low-frequency spontaneous fast intracellular calcium transients. Microtubule stabilization with taxol treatment prevents actin remodeling and nucleokinesis, whereas cells with a collapsed microtubule cytoskeleton induced by nocodazole treatment, display nearly normal actin dynamics and nucleokinesis. In summary, the results presented here demonstrate that actomyosin forces acting at the rear side of the nucleus drives nucleokinesis in tangentially migrating interneurons in a process that requires calcium and a dynamic cytoskeleton of microtubules.
Regulation of Cortical Actin Networks in Cell Migration
International Review of Cytology-a Survey of Cell Biology, 2003
The actin cytoskeleton is a primary determinant of cell shape and motility. Studies on actin regulatory proteins are now coupled with studies of the signal transduction that directs actin cytoskeleton reorganization, and we have gained insights into how external stimuli such as chemoattractants drive changes in actin cytoskeleton. Chemoattractants regulate actin regulatory proteins such as the Arp2⧸3 complex through WASP family proteins, ADF⧸cofilin downstream of LIM-kinase, and various other phosphoinositide-dependent or -independent pathways. Through branching of actin filaments, Arp2⧸3 complex-dependent actin polymerization is suffcient to generate the force necessary for protrusion.
Frontiers in Cellular Neuroscience, 2014
Disrupted-in-Schizophrenia 1 (DISC1) is a risk gene for a spectrum of major mental disorders. It has been shown to regulate radial migration as well as dendritic arborization during neurodevelopment and corticogenesis. In a previous study we demonstrated through in vitro experiments that DISC1 also controls the tangential migration of cortical interneurons originating from the medial ganglionic eminence (MGE). Here we first show that DISC1 is necessary for the proper tangential migration of cortical interneurons in the intact brain. Expression of EGFP under the Lhx6 promotor allowed us to analyze exclusively interneurons transfected in the MGE after in utero electroporation. After 3 days in utero, DISC1 deficient interneurons displayed prolonged leading processes and, compared to control, fewer neurons reached the cortex. Time-lapse video microscopy of cortical feeder-layers revealed a decreased migration velocity due to a reduction of soma translocations. Immunostainings indicated that DISC1 is co-localized with F-actin in the growth cone-like structure of the leading process. DISC1 knockdown reduced F-actin levels whereas the overall actin level was not altered. Moreover, DISC1 knockdown also decreased levels of phosphorylated Girdin, which cross-links F-actin, as well as the Girdin-activator pAkt. In contrast, using time-lapse video microscopy of fluorescence-tagged tubulin and EB3 in fibroblasts, we found no effects on microtubule polymerization when DISC1 was reduced. However, DISC1 affected the acetylation of microtubules in the leading processes of MGE-derived cortical interneurons. Together, our results provide a mechanism how DISC1 might contribute to interneuron migration thereby explaining the reduced number of specific classes of cortical interneurons in some DISC1 mouse models.
A role for mDia, a Rho-regulated actin nucleator, in tangential migration of interneuron precursors
Nature Neuroscience, 2012
In brain development, excitatory and inhibitory neurons show distinct types of migration, radial migration and tangential migration, respectively. Whether these two types of migration are operated by similar cellular mechanisms remains unclear. Here we examined mice deficient in mDia, a Rho-regulated actin nucleator, in neuronal migration. mDia deficiency impaired tangential migration of cortical and olfactory inhibitory interneurons, whereas radial migration and consequent layer formation of cortical excitatory neurons were unaffected. mDia-deficient neuroblasts exhibited reduced separation of the centrosome from the nucleus and retarded nuclear translocation. Concomitantly, anterograde F-actin movement and the following rear F-actin condensation that occur during centrosomal and nuclear movement of wild-type cells, respectively, were impaired in mDia-deficient neuroblasts. Blockade of ROCK, another Rho effector regulating myosin II, also impaired nuclear translocation. These results suggest that the Rho-mDia/ROCK signaling critically regulates nuclear translocation via F-actin dynamics in tangential migration, while this mechanism is dispensable in radial migration.
Coordination of Actin Filament and Microtubule Dynamics during Neurite Outgrowth
Developmental Cell, 2008
Although much evidence suggests that axon growth and guidance depend on well-coordinated cytoskeletal dynamics, direct characterization of the corresponding molecular events has remained a challenge. Here, we address this outstanding problem by examining neurite outgrowth stimulated by local application of cell adhesion substrates. During acute outgrowth, the advance of organelles and underlying microtubules into the central domain was correlated with regions of attenuated retrograde actin network flow in the periphery. Interestingly, as adhesion sites matured, contractile actin arc structures, known to be regulated by the Rho/Rho Kinase/myosin II signaling cascade, became more robust and coordinated microtubule movements in the growth cone neck. When Rho Kinase was inhibited, although growth responses occurred with less of a delay, microtubules failed to consolidate into a single axis of growth. These results reveal a new role for Rho Kinase and myosin II contractility in regulation of microtubule behavior during neuronal growth.
ABSTRACTInterneuron development is a crucial step of brain corticogenesis. When affected it often leads to brain dysfunctions, such as epilepsy, intellectual disabilities and autism spectrum disorder. Such defects are observed in theDYRK1A-haploinsufficiency syndrome, caused by mutations ofDYRK1A, and commonly associated to cortical excitatory/inhibitory imbalance. However, how this imbalance is established in this syndrome remains elusive. Here, using mouse models and live imaging, we show thatDyrk1aspecifically regulates the development of the cortical GABAergic system. Unlike projection excitatory neurons, we demonstrate that interneuron tangential migration relies on Dyrk1a dosage and kinase activity through a mechanism involving actomyosin cytoskeleton remodeling. Interestingly, we further demonstrate that mice with heterozygous inactivation ofDyrk1ain interneurons show behavioral defects and epileptic activity, recapitulating phenotypes observed in human patients. Altogether, ...
Radial contractility of actomyosin rings facilitates axonal trafficking and structural stability
Journal of Cell Biology, 2020
Most mammalian neurons have a narrow axon, which constrains the passage of large cargoes such as autophagosomes that can be larger than the axon diameter. Radial axonal expansion must therefore occur to ensure efficient axonal trafficking. In this study, we reveal that the speed of various large cargoes undergoing axonal transport is significantly slower than that of small ones and that the transit of diverse-sized cargoes causes an acute, albeit transient, axonal radial expansion, which is immediately restored by constitutive axonal contractility. Using live super-resolution microscopy, we demonstrate that actomyosin-II controls axonal radial contractility and local expansion, and that NM-II filaments associate with periodic F-actin rings via their head domains. Pharmacological inhibition of NM-II activity significantly increases axon diameter by detaching the NM-II from F-actin and impacts the trafficking speed, directionality, and overall efficiency of long-range retrograde traff...
Cell-Intrinsic Control of Interneuron Migration Drives Cortical Morphogenesis
Cell, 2018
Interneurons navigate along multiple tangential paths to settle into appropriate cortical layers. They undergo a saltatory migration paced by intermittent nuclear jumps whose regulation relies on interplay between extracellular cues and genetic-encoded information. It remains unclear how cycles of pause and movement are coordinated at the molecular level. Post-translational modification of proteins contributes to cell migration regulation. The present study uncovers that carboxypeptidase 1, which promotes post-translational protein deglutamylation, controls the pausing of migrating cortical interneurons. Moreover, we demonstrate that pausing during migration attenuates movement simultaneity at the population level, thereby controlling the flow of interneurons invading the cortex. Interfering with the regulation of pausing not only affects the size of the cortical interneuron cohort but also impairs the generation of age-matched projection neurons of the upper layers.
Developmental Cell, 2012
The migration of cortical interneurons is characterized by extensive morphological changes that result from successive cycles of nucleokinesis and neurite branching. Their molecular bases remain elusive, and the present work describes how p27 Kip1 controls cell-cycle-unrelated signaling pathways to regulate these morphological remodelings. Live imaging reveals that interneurons lacking p27 Kip1 show delayed tangential migration resulting from defects in both nucleokinesis and dynamic branching of the leading process. At the molecular level, p27 Kip1 is a microtubule-associated protein that promotes polymerization of microtubules in extending neurites, thereby contributing to tangential migration. Furthermore, we show that p27 Kip1 controls actomyosin contractions that drive both forward translocation of the nucleus and growth cone splitting. Thus, p27 Kip1 cell-autonomously controls nucleokinesis and neurite branching by regulating both actin and microtubule cytoskeletons.