RESUMEN
Heterogeneous nuclear ribonucleoproteins (hnRNPs) constitute a family of multifunctional RNA-binding proteins able to process nuclear pre-mRNAs into mature mRNAs and regulate gene expression in multiple ways. They comprise at least 20 different members in mammals, named from A (HNRNP A1) to U (HNRNP U). Many of these proteins are components of the spliceosome complex and can modulate alternative splicing in a tissue-specific manner. Notably, while genes encoding hnRNPs exhibit ubiquitous expression, increasing evidence associate these proteins to various neurodevelopmental and neurodegenerative disorders, such as intellectual disability, epilepsy, microcephaly, amyotrophic lateral sclerosis, or dementias, highlighting their crucial role in the central nervous system. This review explores the evolution of the hnRNPs family, highlighting the emergence of numerous new members within this family, and sheds light on their implications for brain development.
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The ADAT2/ADAT3 complex catalyzes the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3 , the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders (NDDs). Yet, the physiological function of ADAT2/ADAT3 complex during brain development remains totally unknown. Here we showed that maintaining a proper level of ADAT2/ADAT3 catalytic activity is required for correct radial migration of projection neurons in the developing mouse cortex. In addition, we not only reported 7 new NDD patients carrying biallelic variants in ADAT3 but also deeply characterize the impact of those variants on ADAT2/ADAT3 structure, biochemical properties, enzymatic activity and tRNAs editing and abundance. We demonstrated that all the identified variants alter both the expression and the activity of the complex leading to a significant decrease of I 34 with direct consequence on their steady-state. Using in vivo complementation assays, we correlated the severity of the migration phenotype with the degree of the loss of function caused by the variants. Altogether, our results indicate a critical role of ADAT2/ADAT3 during cortical development and provide cellular and molecular insights into the pathogenicity of ADAT3-related neurodevelopmental disorder.
RESUMEN
Completion of neuronal migration is critical for brain development. Kif21b is a plus-end-directed kinesin motor protein that promotes intracellular transport and controls microtubule dynamics in neurons. Here we report a physiological function of Kif21b during radial migration of projection neurons in the mouse developing cortex. In vivo analysis in mouse and live imaging on cultured slices demonstrate that Kif21b regulates the radial glia-guided locomotion of newborn neurons independently of its motility on microtubules. We show that Kif21b directly binds and regulates the actin cytoskeleton both in vitro and in vivo in migratory neurons. We establish that Kif21b-mediated regulation of actin cytoskeleton dynamics influences branching and nucleokinesis during neuronal locomotion. Altogether, our results reveal atypical roles of Kif21b on the actin cytoskeleton during migration of cortical projection neurons.
Asunto(s)
Cinesinas , Neuronas , Animales , Ratones , Citoesqueleto de Actina/metabolismo , Movimiento Celular , Interneuronas/metabolismo , Cinesinas/metabolismo , Microtúbulos/metabolismo , Neuronas/metabolismoRESUMEN
Kinesin Family Member 21B (KIF21B) encoded by KIF21B (MIM*608322), belongs to the Kinesin superfamily proteins, which play a key role in microtubule organisation in neuronal dendrites and axons. Recently, heterozygous variants in KIF21B were implicated as the cause of intellectual disability and brain malformations in four unrelated individuals. We report a 9-year-old male with delayed speech, hyperactivity, poor social interaction, and autistic features. A parent-offspring trio exome sequencing identified a novel de novo rare heterozygous variant, NM_001252102.2: c.1513A>C, p.(Ser505Arg) in exon 11 of KIF21B. In vivo functional analysis using in utero electroporation in mouse embryonic cortex revealed that the expression of Ser505Arg KIF21B protein in the cerebral cortex impaired the radial migration of projection neurons, thus confirming the pathogenicity of the variant. Our report further validates pathogenic variants in KIF21B as a cause of neurodevelopmental disorder.
Asunto(s)
Discapacidad Intelectual , Trastornos del Neurodesarrollo , Masculino , Animales , Ratones , Cinesinas/genética , Neuronas/metabolismo , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Axones , Corteza Cerebral/patología , Discapacidad Intelectual/patologíaRESUMEN
Post-transcriptional modification of tRNA wobble adenosine into inosine is crucial for decoding multiple mRNA codons by a single tRNA. The eukaryotic wobble adenosine-to-inosine modification is catalysed by the ADAT (ADAT2/ADAT3) complex that modifies up to eight tRNAs, requiring a full tRNA for activity. Yet, ADAT catalytic mechanism and its implication in neurodevelopmental disorders remain poorly understood. Here, we have characterized mouse ADAT and provide the molecular basis for tRNAs deamination by ADAT2 as well as ADAT3 inactivation by loss of catalytic and tRNA-binding determinants. We show that tRNA binding and deamination can vary depending on the cognate tRNA but absolutely rely on the eukaryote-specific ADAT3 N-terminal domain. This domain can rotate with respect to the ADAT catalytic domain to present and position the tRNA anticodon-stem-loop correctly in ADAT2 active site. A founder mutation in the ADAT3 N-terminal domain, which causes intellectual disability, does not affect tRNA binding despite the structural changes it induces but most likely hinders optimal presentation of the tRNA anticodon-stem-loop to ADAT2.
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Adenosina Desaminasa/química , Adenosina/metabolismo , Adenosina Desaminasa/genética , Adenosina Desaminasa/metabolismo , Animales , Dominio Catalítico , Línea Celular Tumoral , Movimiento Celular , Cristalografía por Rayos X , Ferredoxinas/química , Inosina/metabolismo , Ratones , Modelos Moleculares , Mutación , Neuronas/fisiología , Dominios Proteicos , ARN de Transferencia/química , ARN de Transferencia/metabolismoRESUMEN
KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients' neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder.
Asunto(s)
Cinesinas/genética , Actividad Motora , Mutación/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/fisiopatología , Animales , Axones/metabolismo , Movimiento Celular , Proliferación Celular , Corteza Cerebral/embriología , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Femenino , Regulación del Desarrollo de la Expresión Génica , Células HEK293 , Humanos , Masculino , Ratones , Mutación Missense/genética , Red Nerviosa/patología , Red Nerviosa/fisiopatología , Neuronas/metabolismo , Tamaño de los Órganos , Organogénesis/genética , Linaje , ARN Mensajero/genética , ARN Mensajero/metabolismo , Pez Cebra/anatomía & histología , Pez Cebra/genéticaRESUMEN
De novo heterozygous missense variants in the γ-tubulin gene TUBG1 have been linked to human malformations of cortical development associated with intellectual disability and epilepsy. Here, we investigated through in-utero electroporation and in-vivo studies, how four of these variants affect cortical development. We show that TUBG1 mutants affect neuronal positioning, disrupting the locomotion of new-born neurons but without affecting progenitors' proliferation. We further demonstrate that pathogenic TUBG1 variants are linked to reduced microtubule dynamics but without major structural nor functional centrosome defects in subject-derived fibroblasts. Additionally, we developed a knock-in Tubg1Y92C/+ mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1Y92C/+ animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1Y92C/+ mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations.
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Malformaciones del Desarrollo Cortical/genética , Microtúbulos/metabolismo , Neurogénesis/genética , Neuronas/fisiología , Tubulina (Proteína)/genética , Animales , Conducta Animal , Movimiento Celular/genética , Centrosoma/metabolismo , Corteza Cerebral/anomalías , Corteza Cerebral/citología , Corteza Cerebral/diagnóstico por imagen , Modelos Animales de Enfermedad , Embrión de Mamíferos , Epilepsia/genética , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Fibroblastos/ultraestructura , Técnicas de Sustitución del Gen , Predisposición Genética a la Enfermedad , Células HeLa , Humanos , Microscopía Intravital , Masculino , Ratones , Ratones Transgénicos , Microscopía Confocal , Microscopía Electrónica , Microtúbulos/genética , Mutación MissenseRESUMEN
The protein p27Kip1 plays roles that extend beyond cell-cycle regulation during cerebral cortex development, such as the regulation of neuronal migration and neurite branching via signaling pathways that converge on the actin and microtubule cytoskeletons. Microtubule-dependent transport is essential for the maturation of neurons and the establishment of neuronal connectivity though synapse formation and maintenance. Here, we show that p27Kip1 controls the transport of vesicles and organelles along the axon of mice cortical projection neurons in vitro. Moreover, suppression of the p27Kip1 ortholog, dacapo, in Drosophila melanogaster disrupts axonal transport in vivo, leading to the reduction of locomotor activity in third instar larvae and adult flies. At the molecular level, p27Kip1 stabilizes the α-tubulin acetyltransferase 1, thereby promoting the acetylation of microtubules, a post-translational modification required for proper axonal transport.
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Acetiltransferasas/metabolismo , Transporte Axonal , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Microtúbulos/metabolismo , Proteínas Nucleares/metabolismo , Acetilación , Animales , Drosophila melanogaster/metabolismo , Estabilidad de Enzimas , Femenino , Células HEK293 , Histona Desacetilasa 6/metabolismo , Humanos , Masculino , Ratones , Microtúbulos/metabolismo , Modelos Biológicos , Actividad Motora , Neuronas/metabolismo , Unión ProteicaRESUMEN
Genetic findings reported by our group and others showed that de novo missense variants in the KIF2A gene underlie malformations of brain development called pachygyria and microcephaly. Though KIF2A is known as member of the Kinesin-13 family involved in the regulation of microtubule end dynamics through its ATP dependent MT-depolymerase activity, how KIF2A variants lead to brain malformations is still largely unknown. Using cellular and in utero electroporation approaches, we show here that KIF2A disease-causing variants disrupts projection neuron positioning and interneuron migration, as well as progenitors proliferation. Interestingly, further dissection of this latter process revealed that ciliogenesis regulation is also altered during progenitors cell cycle. Altogether, our data suggest that deregulation of the coupling between ciliogenesis and cell cycle might contribute to the pathogenesis of KIF2A-related brain malformations. They also raise the issue whether ciliogenesis defects are a hallmark of other brain malformations, such as those related to tubulins and MT-motor proteins variants.
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Cilios/genética , Cinesinas/metabolismo , Malformaciones del Desarrollo Cortical/genética , Proteínas Represoras/metabolismo , Animales , Encéfalo/metabolismo , Ciclo Celular/genética , Cilios/fisiología , Células HeLa , Humanos , Cinesinas/genética , Malformaciones del Desarrollo Cortical/metabolismo , Ratones , Microcefalia/metabolismo , Microtúbulos/metabolismo , Neurogénesis , Proteínas Represoras/genética , Huso Acromático/metabolismo , Tubulina (Proteína)/metabolismoRESUMEN
The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker (Atg16l1, Coro1c, Dmxl2, and Herc1), thinner (Kif21b and Wdr89), or absent corpus callosum (Wdr47), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking Wdr47 showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy.
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Autofagia/fisiología , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Proteínas de Microfilamentos/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Repeticiones WD40/fisiología , Animales , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Células Cultivadas , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Microtúbulos/metabolismo , Microtúbulos/fisiología , Neurogénesis/fisiología , Neuronas/metabolismo , Neuronas/fisiología , Fenotipo , Células Madre/metabolismo , Células Madre/fisiologíaRESUMEN
Neurodevelopmental disorders with periventricular nodular heterotopia (PNH) are etiologically heterogeneous, and their genetic causes remain in many cases unknown. Here we show that missense mutations in NEDD4L mapping to the HECT domain of the encoded E3 ubiquitin ligase lead to PNH associated with toe syndactyly, cleft palate and neurodevelopmental delay. Cellular and expression data showed sensitivity of PNH-associated mutants to proteasome degradation. Moreover, an in utero electroporation approach showed that PNH-related mutants and excess wild-type NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin-based experiments, found differential deregulation of pathways involved. Excess wild-type NEDD4L leads to disruption of Dab1 and mTORC1 pathways, while PNH-related mutations are associated with deregulation of mTORC1 and AKT activities. Altogether, these data provide insights into the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development.
Asunto(s)
Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Mutación Missense , Heterotopia Nodular Periventricular/genética , Ubiquitina-Proteína Ligasas/genética , Animales , Células Cultivadas , Femenino , Humanos , Masculino , Ratones , Ubiquitina-Proteína Ligasas Nedd4 , Dominios Proteicos/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Ubiquitina/metabolismoRESUMEN
The migration of cortical interneurons is a fundamental process for the establishment of cortical connectivity and its impairment underlies several neurological disorders. During development, these neurons are born in the ganglionic eminences and they migrate tangentially to populate the cortical layers. This process relies on various morphological changes that are driven by dynamic cytoskeleton remodelings. By coupling time lapse imaging with molecular analyses, we show that the Elongator complex controls cortical interneuron migration in mouse embryos by regulating nucleokinesis and branching dynamics. At the molecular level, Elongator fine-tunes actomyosin forces by regulating the distribution and turnover of actin microfilaments during cell migration. Thus, we demonstrate that Elongator cell-autonomously promotes cortical interneuron migration by controlling actin cytoskeletal dynamics.
Asunto(s)
Actomiosina/metabolismo , Corteza Cerebral/metabolismo , Histona Acetiltransferasas/genética , Animales , Movimiento Celular , Células Cultivadas , Células HEK293 , Histona Acetiltransferasas/antagonistas & inhibidores , Histona Acetiltransferasas/metabolismo , Humanos , Técnicas In Vitro , Interneuronas/citología , Interneuronas/metabolismo , Proteínas con Homeodominio LIM/metabolismo , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Fosfoproteínas Fosfatasas/antagonistas & inhibidores , Fosfoproteínas Fosfatasas/genética , Fosfoproteínas Fosfatasas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Imagen de Lapso de Tiempo , Factores de Transcripción/metabolismoRESUMEN
Some mutations of the LRRK2 gene underlie autosomal dominant form of Parkinson's disease (PD). The G2019S is a common mutation that accounts for about 2% of PD cases. To understand the pathophysiology of this mutation and its possible developmental implications, we developed an in vitro assay to model PD with human induced pluripotent stem cells (hiPSCs) reprogrammed from skin fibroblasts of PD patients suffering from the LRKK2 G2019S mutation. We differentiated the hiPSCs into neural stem cells (NSCs) and further into dopaminergic neurons. Here we show that NSCs bearing the mutation tend to differentiate less efficiently into dopaminergic neurons and that the latter exhibit significant branching defects as compared to their controls.
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Neuronas Dopaminérgicas/citología , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/enzimología , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Mutación/genética , Neuritas/metabolismo , Animales , Células Cultivadas , Humanos , Mesencéfalo/citología , Ratones , Células-Madre Neurales/citología , Enfermedad de Parkinson/genética , FenotipoAsunto(s)
Corteza Cerebral/fisiología , Estrés del Retículo Endoplásmico/fisiología , Neurogénesis/fisiología , Respuesta de Proteína Desplegada/fisiología , Animales , Corteza Cerebral/citología , Retículo Endoplásmico/metabolismo , Humanos , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Neurogénesis/genética , Neuronas/metabolismo , Neuronas/fisiología , Estrés Fisiológico/fisiologíaRESUMEN
The unfolded protein response (UPR) is a homeostatic signaling pathway triggered by protein misfolding in the endoplasmic reticulum (ER). Beyond its protective role, it plays important functions during normal development in response to elevated demand for protein folding. Several UPR effectors show dynamic temporal and spatial expression patterns that correlate with milestones of the central nervous system (CNS) development. Here, we discuss recent studies suggesting that a dynamic regulation of UPR supports generation, maturation, and maintenance of differentiated neurons in the CNS. We further highlight studies supporting a developmental vulnerability of CNS to UPR dysregulation, which underlies neurodevelopmental disorders. We believe that a better understanding of UPR functions may provide novel opportunities for therapeutic strategies to fight ER/UPR-associated human neurological disorders.
Asunto(s)
Homeostasis/fisiología , Sistema Nervioso/metabolismo , Pliegue de Proteína , Transducción de Señal/fisiología , Respuesta de Proteína Desplegada/fisiología , Animales , Retículo Endoplásmico/metabolismo , HumanosRESUMEN
The cerebral cortex is one of the most intricate regions of the brain that requires elaborate cell migration patterns for its development. Experimental observations show that projection neurons migrate radially within the cortical wall, whereas interneurons migrate along multiple tangential paths to reach the developing cortex. Tight regulation of the cell migration processes ensures proper positioning and functional integration of neurons to specific cerebral cortical circuits. Disruption of neuronal migration often leads to cortical dysfunction and/or malformation associated with neurological disorders. Unveiling the molecular control of neuron migration is thus fundamental to understanding the physiological or pathological development of the cerebral cortex. In this unit, protocols allowing detailed analysis of patterns of migration of both interneurons and projection neurons under different experimental conditions (i.e., loss or gain of function) are presented.
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Movimiento Celular/fisiología , Corteza Cerebral/fisiología , Neuronas/fisiología , Neurociencias/métodos , Animales , Corteza Cerebral/citología , Proteínas Fluorescentes Verdes/metabolismo , Integrasas/metabolismo , Interneuronas/fisiología , Sustancias Luminiscentes/metabolismo , RatonesRESUMEN
The cerebral cortex contains layers of neurons sequentially generated by distinct lineage-related progenitors. At the onset of corticogenesis, the first-born progenitors are apical progenitors (APs), whose asymmetric division gives birth directly to neurons. Later, they switch to indirect neurogenesis by generating intermediate progenitors (IPs), which give rise to projection neurons of all cortical layers. While a direct lineage relationship between APs and IPs has been established, the molecular mechanism that controls their transition remains elusive. Here we show that interfering with codon translation speed triggers ER stress and the unfolded protein response (UPR), further impairing the generation of IPs and leading to microcephaly. Moreover, we demonstrate that a progressive downregulation of UPR in cortical progenitors acts as a physiological signal to amplify IPs and promotes indirect neurogenesis. Thus, our findings reveal a contribution of UPR to cell fate acquisition during mammalian brain development.
Asunto(s)
Corteza Cerebral/embriología , Regulación del Desarrollo de la Expresión Génica , Histona Acetiltransferasas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neurogénesis/fisiología , Respuesta de Proteína Desplegada , Animales , Linaje de la Célula , Separación Celular , Corteza Cerebral/metabolismo , Codón , Drosophila melanogaster , Células Madre Embrionarias/citología , Eliminación de Gen , Genotipo , Histona Acetiltransferasas/genética , Humanos , Ratones , Ratones Noqueados , Neuronas/metabolismo , Fosforilación , Biosíntesis de Proteínas , Desnaturalización Proteica , Pliegue de Proteína , Transducción de Señal , Células Madre/citología , Regulación hacia ArribaRESUMEN
The migration of cortical projection neurons is a multistep process characterized by dynamic cell shape remodeling. The molecular basis of these changes remains elusive, and the present work describes how microRNAs (miRNAs) control neuronal polarization during radial migration. We show that miR-22 and miR-124 are expressed in the cortical wall where they target components of the CoREST/REST transcriptional repressor complex, thereby regulating doublecortin transcription in migrating neurons. This molecular pathway underlies radial migration by promoting dynamic multipolar-bipolar cell conversion at early phases of migration, and later stabilization of cell polarity to support locomotion on radial glia fibers. Thus, our work emphasizes key roles of some miRNAs that control radial migration during cerebral corticogenesis.
Asunto(s)
Movimiento Celular/fisiología , Corteza Cerebral/citología , MicroARNs/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , Proteínas Represoras/metabolismo , Animales , Polaridad Celular/fisiología , Células Cultivadas , Proteínas Co-Represoras , Ratones , Ratones Transgénicos , Neuronas/metabolismoRESUMEN
The cerebral cortex is one of the most intricate regions of the brain, which required elaborated cell migration patterns for its development. Experimental observations show that projection neurons migrate radially within the cortical wall, whereas interneurons migrate along multiple tangential paths to reach the developing cortex. Tight regulation of the cell migration processes ensures proper positioning and functional integration of neurons to specific cerebral cortical circuits. Disruption of neuronal migration often lead to cortical dysfunction and/or malformation associated with neurological disorders. Unveiling the molecular control of neuronal migration is thus fundamental to understand the physiological or pathological development of the cerebral cortex. Generation of functional cortical neurons is a complex and stratified process that relies on decision of neural progenitors to leave the cell cycle and generate neurons that migrate and differentiate to reach their final position in the cortical wall. Although accumulating work shed some light on the molecular control of neuronal migration, we currently do not have a comprehensive understanding of how cell cycle exit and migration/differentiation are coordinated at the molecular level. The current chapter tends to lift the veil on this issue by discussing how core cell cycle regulators, and in particular p27(Kip1) acts as a multifunctional protein to control critical steps of neuronal migration through activities that go far beyond cell cycle regulation.
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Ciclo Celular/fisiología , Movimiento Celular/fisiología , Corteza Cerebral/enzimología , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Neuronas/enzimología , Animales , Corteza Cerebral/citología , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Humanos , Neuronas/citologíaRESUMEN
Huntington disease (HD) is associated with early psychiatric symptoms including anxiety and depression. Here, we demonstrate that wild-type huntingtin, the protein mutated in HD, modulates anxiety/depression-related behaviors according to its phosphorylation at serines 1181 and 1201. Genetic phospho-ablation at serines 1181 and 1201 in mouse reduces basal levels of anxiety/depression-like behaviors. We observe that the reduction in anxiety/depression-like phenotypes is associated with increased adult hippocampal neurogenesis. By improving the attachment of molecular motors to microtubules, huntingtin dephosphorylation increases axonal transport of BDNF, a crucial factor for hippocampal adult neurogenesis. Consequently, the huntingtin-mediated increased BDNF dynamics lead to an increased delivery and signaling of hippocampal BDNF. These results support the notion that huntingtin participates in anxiety and depression-like behavior and is thus relevant to the etiology of mood disorders and anxiety/depression in HD.