Figure 1 - available from: neurogenetics
This content is subject to copyright. Terms and conditions apply.
Classic lissencephaly caused by KIF2A mutations. Each row shows multiple images from the same patient. Midline sagittal (far left column), parasagittal (second column), T1-weighted MRI images. Axial T2-weighted images through the deep nuclei (center column) and bodies of the lateral ventricles (fourth column) and coronal images through the hippocampus (far right column). All three have frontal pachygyria and posterior agyria consistent with classic LIS grade 3 and a posterior more severe than anterior (p > a) gradient. Wide shallow sylvian fissures create a figure-of-eight appearance (D, I, N). The thickness of the cortex is over 10 mm. A high-intensity (white) line (arrow heads) beneath the cerebral surface is consistent with a cell-sparse layer of the four-layered cortex. Corpus callosum is dysmorphic (A) and thin (F, K). Pons and cerebellum are normal. This appearance is essentially identical to patients with LIS1 mutations and deletions. These images are from patient 1 (A–E) aged 7 months, P462 (F–J) aged 1 month, and P147 (K–O) aged 7 years
Source publication
Kinesins play a critical role in the organization and dynamics of the microtubule cytoskeleton, making them central players in neuronal proliferation, neuronal migration, and postmigrational development. Recently, KIF2A mutations were identified in cortical malformation syndromes associated with microcephaly. Here, we detected two de novo p.Ser317A...
Similar publications
Kinesin-13 proteins are major microtubule (MT) regulatory factors that catalyze removal of tubulin subunits from MT ends. The class-specific "neck" and loop 2 regions of these motors are required for MT depolymerization, but their contributing roles are still unresolved because their interactions with MT ends have not been observed directly. Here w...
Citations
... New neurons are generated in the ventricular zone (VZ) or subventricular zone (SVZ) from where they migrate in parallel to basal processes of radial glia to the appropriate cortical layer (Hakanen et al., 2019). KIF2A mutations were associated with several MCD, among which lissencephaly, pachygyria, and heterotopia are directly linked to defective radial migration of neurons (Poirier et al., 2013;Parrini et al., 2016;Tian et al., 2016;Cavallin et al., 2017). This is the case for instance of two de novo mutations namely, p.Ser317Asn and p.His321Pro that cause type 1 lissencephaly ( Table 1; Cavallin et al., 2017). ...
... KIF2A mutations were associated with several MCD, among which lissencephaly, pachygyria, and heterotopia are directly linked to defective radial migration of neurons (Poirier et al., 2013;Parrini et al., 2016;Tian et al., 2016;Cavallin et al., 2017). This is the case for instance of two de novo mutations namely, p.Ser317Asn and p.His321Pro that cause type 1 lissencephaly ( Table 1; Cavallin et al., 2017). Mice expressing these variants exhibit abnormal radial migration of glutamatergic neurons and altered lamination of the cerebral cortex (Gilet et al., 2020). ...
... In humans, KIF2A mutations result in MCD, epilepsy, and autism spectrum disorder (Poirier et al., 2013;Yuen et al., 2015;Tian et al., 2016;Cavallin et al., 2017;Costain et al., 2019;Hatano et al., 2021). The clinical features vary according to the mutated region ( Figure 1A and Table 1). ...
Microtubules play a central role in cytoskeletal changes during neuronal development and maintenance. Microtubule dynamics is essential to polarity and shape transitions underlying neural cell division, differentiation, motility, and maturation. Kinesin superfamily protein 2A is a member of human kinesin 13 gene family of proteins that depolymerize and destabilize microtubules. In dividing cells, kinesin superfamily protein 2A is involved in mitotic progression, spindle assembly, and chromosome segregation. In postmitotic neurons, it is required for axon/dendrite specification and extension, neuronal migration, connectivity, and survival. Humans with kinesin superfamily protein 2A mutations suffer from a variety of malformations of cortical development, epilepsy, autism spectrum disorder, and neurodegeneration. In this review, we discuss how kinesin superfamily protein 2A regulates neuronal development and function, and how its deregulation causes neurodevelopmental and neurological disorders.
... nucleotide-binding domain were associated with malformations of cortical development, including microcephaly, lissencephaly, and partial agenesis of the corpus callosum (CC; [22][23][24][25]. Variants in the motor domain were associated with epilepsy, and variants in other domains were associated with autism spectrum disorder (25)(26)(27). ...
KIF2A is an atypical kinesin that has the capacity to depolymerize microtubules. Patients carrying mutations in KIF2A suffer from progressive microcephaly and mental disabilities. While the role of this protein is well documented in neuronal migration, the relationship between its dysfunction and the pathobiology of brain disorders is unclear. Here, we report that KIF2A is dispensable for embryogenic neurogenesis but critical in postnatal stages for maturation, connectivity, and maintenance of neurons. We used a conditional approach to inactivate KIF2A in cortical progenitors, nascent postmitotic neurons, and mature neurons in mice. We show that the lack of KIF2A alters microtubule dynamics and disrupts several microtubule-dependent processes, including neuronal polarity, neuritogenesis, synaptogenesis, and axonal transport. KIF2A-deficient neurons exhibit aberrant electrophysiological characteristics, neuronal connectivity, and function, leading to their loss. The role of KIF2A is not limited to development, as fully mature neurons require KIF2A for survival. Our results emphasize an additional function of KIF2A and help explain how its mutations lead to brain disorders.
... LIS1 mutations result in a more severe phenotype in the parietal and occipital cortex, whereas in the case of mutations in DCX, the malformation is more pronounced in the frontal cortex [167,168]. A smooth cerebral surface with a posterior-to-anterior gradient of severity was noted in cases of mutations in ARX [169,170], KIF2A [171], MACF1 [172], DYNC1H1 [173][174][175]. The same trend was noted for mutations in several tubulin genes; TUBA1A [176][177][178], TUBG1 [179], TUBB2B, TUBB3 [180], TUBB5 [181], TUBA8 [182]. ...
The cortex is a highly organized structure that develops from the caudal regions of the segmented neural tube. Its spatial organization sets the stage for future functional arealization. Here, we suggest using a developmental perspective to describe and understand the etiology of common cortical malformations and their manifestation in the human brain.
... KIF2A, a microtubule (MT)-depolymerizing kinesin, functions in mitotic spindle assembly (Ganem and Compton, 2004) and primary cilium disassembly in mitotic cells (Miyamoto et al., 2015;Zhang et al., 2019), and in axonal pruning in differentiating neurons (Homma et al., 2018;Maor-Nof et al., 2013). In humans, mutations in the motor domain of KIF2A are causative for malformations of cortical development, manifesting as lissencephaly, microcephaly, pachygyria and heterotopias (Broix et al., 2018;Cavallin et al., 2017;Poirier et al., 2013;Tian et al., 2016). Recent studies have suggested that Kif2a AS is regulated by neuron-specific RNAbinding proteins (Ince- Dunn et al., 2012) and its isoform abundance dynamically shifts during the neural progenitor-to-neuron transition during development of the cerebral cortex (Zhang et al., 2016). ...
... Mutations in the ATP binding sites of the KIF2A motor domain cause malformations of cortical development (Broix et al., 2018;Cavallin et al., 2017;Poirier et al., 2013;Tian et al., 2016). Patients manifest with a spectrum of symptoms which may include frontal band heterotopia, pachygyria, microcephaly, lissencephaly and neonatal onset seizure (Broix et al., 2018;Cavallin et al., 2017;Poirier et al., 2013;Tian et al., 2016). ...
... Mutations in the ATP binding sites of the KIF2A motor domain cause malformations of cortical development (Broix et al., 2018;Cavallin et al., 2017;Poirier et al., 2013;Tian et al., 2016). Patients manifest with a spectrum of symptoms which may include frontal band heterotopia, pachygyria, microcephaly, lissencephaly and neonatal onset seizure (Broix et al., 2018;Cavallin et al., 2017;Poirier et al., 2013;Tian et al., 2016). These mutations have been associated with severe migration defects of neurons in the developing cortex and defects in the MT depolymerization activity of KIF2A (Broix et al., 2018;Gilet et al., 2020), ability to regulate the structure and function of the MT-based structure the primary cilium and cell cycle defects in cortical neural progenitors (Broix et al., 2018). ...
KIF2A is a kinesin motor protein with essential roles in neural progenitor division and axonal pruning during brain development. However, how different KIF2A alternative isoforms function during development of the cerebral cortex is not known. Here, we focus on three Kif2a isoforms expressed in the developing cortex. We show that Kif2a is essential for dendritic arborization in mice and that the functions of all three isoforms are sufficient for this process. Interestingly, only two of the isoforms can sustain radial migration of cortical neurons while a third isoform, lacking a key N-terminal region, is ineffective. By proximity-based interactome mapping for individual isoforms, we identify previously known KIF2A interactors, proteins localized to the mitotic spindle poles, and unexpectedly, also translation factors, ribonucleoproteins and proteins that are targeted to organelles, prominently to the mitochondria. In addition, we show that a KIF2A mutation, which causes brain malformations in humans, has extensive changes to its proximity-based interactome, with depletion of mitochondrial proteins identified in the wild-type KIF2A interactome. Our data raises new insights about the importance of alternative splice variants during brain development.
... This could contribute to the prevalence of qNSCs in the postischemic monkey SVZa. A strong postischemic enhancement in the EL was observed for the Kinesin Family Member 2A (KIF2A), a mitotic spindle regulator (Wordeman and Mitchison, 1995) involved in human cortical development (Cavallin et al., 2017). Another interesting example was the transcription factor Myc-Associated Factor X (MAX). ...
The main stem cell niche for neurogenesis in the adult mammalian brain is the subventricular zone (SVZ) that extends along the cerebral lateral ventricles. We aimed at characterizing the initial molecular responses of the macaque monkey SVZ to transient, global cerebral ischemia. We microdissected tissue lining the anterior horn of the lateral ventricle (SVZa) from 7 day post-ischemic and sham-operated monkeys. Transcriptomics shows that in ischemic SVZa, 541 genes were upregulated and 488 genes were down-regulated. The transcription data encompassing the upregulated genes revealed a profile typical for quiescent stem cells and astrocytes. In the primate brain the SVZ is morphologically subdivided in distinct and separate ependymal and subependymal regions. The subependymal contains predominantly neural stem cells (NSC) and differentiated progenitors. To determine in which SVZa region ischemia had evoked transcriptional upregulation, sections through control and ischemic SVZa were analyzed by high-throughput in situ hybridization for a total of 150 upregulated genes shown in the www.monkey-niche.org image database. The majority of the differentially expressed genes mapped to the subependymal layers on the striatal or callosal aspect of the SVZa. Moreover, a substantial number of upregulated genes was expressed in the ependymal layer, implicating a contribution of the ependyma to stem cell biology. The transcriptome analysis yielded several novel gene markers for primate SVZa including the apelin receptor that is strongly expressed in the primate SVZa niche upon ischemic insult.
... Alterations in one of these processes can lead to malformations of cortical development (MCD), often associated with intellectual disability and pharmaco-resistant epilepsy. Our team and others have previously identified mutations in the KIF2A gene in patients with MCD, diagnosed by magnetic resonance imaging sequences with posterior pachygyria and microcephaly (1)(2)(3). KIF2A encodes for a kinesin from the Kinesin-13 family, implicated in the regulation of microtubule (MT) plus-end dynamics (4,5) and individuals with missense mutations in this gene present cortical gyration abnormalities and microcephaly causing pharmaco-resistant epilepsy and intellectual disability (1)(2)(3). Using in utero electroporation and overexpression approaches, we have recently shown disease causing missense variants disrupt projection neurons positioning, interneuron migration and progenitor proliferation (6). ...
... Our team and others have previously identified mutations in the KIF2A gene in patients with MCD, diagnosed by magnetic resonance imaging sequences with posterior pachygyria and microcephaly (1)(2)(3). KIF2A encodes for a kinesin from the Kinesin-13 family, implicated in the regulation of microtubule (MT) plus-end dynamics (4,5) and individuals with missense mutations in this gene present cortical gyration abnormalities and microcephaly causing pharmaco-resistant epilepsy and intellectual disability (1)(2)(3). Using in utero electroporation and overexpression approaches, we have recently shown disease causing missense variants disrupt projection neurons positioning, interneuron migration and progenitor proliferation (6). Altered neuronal migration dynamics, together with defects in the coupling between cell cycle and ciliogenesis, were suggested to underlie the pathogenesis of the related cortical malformations. ...
... We used KIF2A +/H321D ROSA Cre mice to mimic the patient condition and showed indeed that this model recapitulates several phenotypes identified in human patients with KIF2A mutations. Namely, KIF2A +/H321D ROSA Cre mice present with neuroanatomical defects and significant reduction in brain size, correlating with the microcephaly and subcortical heterotopia described in subjects (1,2). Additionally, these mice displayed hyperactivity and memory deficit, which are a hallmark of mouse models of intellectual disability (20). ...
By using the Cre-mediated genetic switch technology, we were able to successfully generate a conditional knock-in mouse, bearing the KIF2A p.His321Asp missense point variant, identified in a subject with malformations of cortical development. These mice present with neuroanatomical anomalies and microcephaly associated with behavioral deficiencies and susceptibility to epilepsy, correlating with the described human phenotype. Using the flexibility of this model provides, we investigated RosaCre, NestinCre and NexCre driven expression of the mutation to dissect the pathophysiological mechanisms underlying neurodevelopmental cortical abnormalities. We show that expression of the p.His321Asp pathogenic variant increases apoptosis and causes abnormal multipolar to bipolar transition in newborn neurons, providing therefore insights to better understand cortical organization and brain growth defects that characterize KIF2A-related human disorders. We further demonstrate that the observed cellular phenotypes are likely to be linked to deficiency in the microtubule depolymerizing function of KIF2A.
... Similar observations were initially made for Tctex-1 (or DNYLT1), a dynein-associated protein which negatively regulates ciliary disassembly (Li et al., 2011), NDE1 (Kim et al., 2011Doobin et al., 2016), a partner of CPAP involved in severe forms of microcephaly (Alkuraya et al., 2011;Bakircioglu et al., 2011), and more recently for KIF2A (Broix et al., 2018), a kinesin involved in ciliary disassembly upon cell-cycle reentry (Miyamoto et al., 2015) for which mutations were identified in MCD cases (Poirier et al., 2013;Cavallin et al., 2017). ...
Ciliopathies are complex genetic multisystem disorders causally related to abnormal assembly or function of motile or non‐motile cilia. While most human cells possess a non‐motile sensory/primary cilium (PC) during development and/or in adult tissues, motile cilia are restricted to specialized cells. As a result, PC‐associated ciliopathies are characterized by high phenotypic variability with extensive clinical and genetic overlaps. In the present review, we have focused on cerebral developmental anomalies which are commonly found in PC‐associated ciliopathies and which have mostly been linked to Hedgehog signaling defects. In addition, we have reviewed emerging evidence that PC dysfunctions could be directly or indirectly involved in the mechanisms underlying malformations of cerebral cortical development including primary microcephaly. This article is protected by copyright. All rights reserved
... Schematic illustration of common features of classical ciliopathies, and severity of each ciliopathy along a spectrum. From Wheway et al., 2018, Bakircioglu et al., 2011, Cavallin et al., 2017, Poirier et al., 2013. Mutations in Rotatin (RTTN), localized to the basal body, impair primary cilium formation (Kia et al., 2012) and are associated with microcephaly amongst other cortical malformations such as polymicrogyria and subcortical heterotopia (Cavallin et al., 2018, Grandone et al., 2016, Kia et al., 2012, Shamseldin et al., 2015, Wambach et al., 2018. ...
Cerebral cortical development is a finely regulated process, depending on diverse progenitor cells. Abnormal behavior of the latter can give rise to cortical malformations. Mutations in Eml1/EML1 were identified in the HeCo mouse, as well as in three families presenting severe subcortical heterotopia (SH). SH is characterized by the presence of mislocalized neurons in the white matter. At early stages of corticogenesis, abnormally positioned apical radial glia progenitors (aRG) were found cycling outside the proliferative ventricular zone (VZ) in the HeCo cortical wall. I focused my research on characterizing aRG in the VZ to assess why some cells leave this region and thus to further understand SH mechanisms. Combining confocal and electron microscopy (EM), I uncovered abnormalities of centrosomes and primary cilia in Eml1-mutant aRGs: primary cilia are shorter, and often remain basally oriented within vesicles. Searching for Eml1-interacting partners using mass spectrometry (MS), combined with exome sequencing of SH patient DNAs, allowed us to identify a ciliary Eml1-interacting partner, RPGRIP1L, showing mutations in a SH patient. Gene ontology analyses of MS data pointed to Golgi apparatus and protein transport as enriched categories. Indeed, Golgi abnormalities were identified in HeCo aRGs. Altogether, these data indicate that the Golgi-to-primary cilium axis is perturbed in Eml1mutant conditions, pointing to new intracellular pathways involved in severe neurodevelopmental disorders.
... To place these data on nGI, diGI and LF score of the 13 primates studied (summarized in Figure 2g Cavallin et al. (2017). The MR images at the level of the hippocampus are from a 3 -month-old healthy infant (control) (Choe et al., 2013) and from 4 month-(TUBA1A), 9 month-(LIS1 [PAFAH1B1]), 7 month-(KIF2A), and 13 year-(DYNC1H1) old patients (Cavallin et al., 2017). ...
... To place these data on nGI, diGI and LF score of the 13 primates studied (summarized in Figure 2g Cavallin et al. (2017). The MR images at the level of the hippocampus are from a 3 -month-old healthy infant (control) (Choe et al., 2013) and from 4 month-(TUBA1A), 9 month-(LIS1 [PAFAH1B1]), 7 month-(KIF2A), and 13 year-(DYNC1H1) old patients (Cavallin et al., 2017). Two regions of the proisocortex, the cingulate cortex and the insular cortex, are indicated in magenta and orange, respectively. ...
... If the increase in nGI during primate evolution is primarily due to an increase in the degree of folding of the isocortex, then one would expect to find a nearly normal formation of the CiS and LF, but a significant loss of folds in the dorsal isocortex, in human patients with mutations causing gyrencephaly-related malformations. Lissencephaly is a malformation that in severe cases (grade 1) can completely abolish neocortical folding (Cavallin et al., 2017;Kato & Dobyns, 2003), resulting in an unfolded human neocortex or in less severe cases (grades 2-4) a dramatically reduced neocortical folding. We noticed that in grade 1 human lissencephaly (specifically, TUBA1A mutation), despite the lack of dorsal isocortex folding, the LF still exists in principle ( Figure 4) (Cavallin et al., 2017). ...
The neocortex, the seat of higher cognitive functions, exhibits a key feature across mammalian species – a highly variable degree of folding. Within the neocortex, two distinct subtypes of cortical areas can be distinguished, the isocortex and the proisocortex. Here, we have compared specific spatiotemporal aspects of folding between the proisocortex and the isocortex in 13 primates, including human, chimpanzee, and various Old World and New World monkeys. We find that folding at the boundaries of the dorsal isocortex and the proisocortex, which gives rise to the cingulate sulcus and the lateral fissure, is conserved across the primates studied and is therefore referred to as conserved folding. In contrast, the degree of folding within the dorsal isocortex exhibits huge variation across these primates, indicating that this folding, which gives rise to gyri and sulci, is subject to major changes during primate evolution. We therefore refer to the folding within the dorsal isocortex as evolved folding. Comparison of fetal neocortex development in long‐tailed macaque and human reveals that the onset of conserved folding precedes the onset of evolved folding. Moreover, analysis of fetal human neocortex exhibiting lissencephaly, a developmental malformation thought to be mainly due to abnormal neuronal migration, shows that the evolved folding is perturbed more than the conserved folding. Taken together, our study present a two‐step model of folding that pertains to primate neocortex development and evolution. Specifically, our data imply that the conserved folding and the evolved folding constitute two distinct, sequential events.
This article is protected by copyright. All rights reserved.
... There are limited reports on kinesin-related LIS in the literature (15,(82)(83)(84)(85). Thus far, four patients with posterior predominant LIS, normal posterior fossa structures and variable degree of microcephaly were reported to harbour mutations of KIF2A gene involving the Ser317 and His321 residues (postulated mutation hotspots) (15,86). This pattern of LIS is similar to that related to LIS1 gene. ...
... One of the reported patients also has hypoplasia of the corpus callosum (15). All four reported patients have spastic tetraplegia and three out of the four patients have visual symptoms (cortical blindness and nystagmus) (86). KIF2Anull mice were found to have multiple brain abnormalities, including cortical lamination defects (87). ...
Malformations of cortical development (MCD) are a heterogenous group of disorders with diverse genotypic and phenotypic variations. Lissencephaly is a subtype of MCD caused by defect in neuronal migration, which occurs between 12 and 24 weeks of gestation. The continuous advancement in the field of molecular genetics in the last decade has led to identification of at least 19 lissencephaly-related genes, most of which are related to microtubule structural proteins (tubulin) or microtubule-associated proteins (MAPs). The aim of this review article is to bring together current knowledge of gene mutations associated with lissencephaly and to provide a comprehensive genotype-phenotype correlation. Illustrative cases will be presented to facilitate the understanding of the described genotype-phenotype correlation.
