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1.
Cell ; 186(13): 2733-2747, 2023 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-37352835

RESUMEN

The cerebral cortex is the brain's outermost layer. It is responsible for processing motor and sensory information that support high-level cognitive abilities and shape personality. Its development and functional organization strongly rely on cell communication that is established via an intricate system of diffusible signals and physical contacts during development. Interfering with this cellular crosstalk can cause neurodevelopmental disorders. Here, we review how crosstalk between migrating cells and their environment influences cerebral cortex development, ranging from neurogenesis to synaptogenesis and assembly of cortical circuits.


Asunto(s)
Corteza Cerebral , Neurogénesis , Comunicación Celular , Cognición
2.
Cell ; 172(5): 1063-1078.e19, 2018 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-29474907

RESUMEN

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.


Asunto(s)
Movimiento Celular , Corteza Cerebral/citología , Interneuronas/citología , Morfogénesis , Actomiosina/metabolismo , Animales , Carboxipeptidasas/metabolismo , Ciclo Celular , Factores Quimiotácticos/metabolismo , Embrión de Mamíferos/citología , Femenino , Eliminación de Gen , Interneuronas/metabolismo , Ratones , Ratones Noqueados , Quinasa de Cadena Ligera de Miosina/metabolismo , Neurogénesis , Fenotipo
3.
EMBO J ; 43(18): 3916-3947, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39085648

RESUMEN

Intestinal tuft cells are critical for anti-helminth parasite immunity because they produce IL-25, which triggers IL-13 secretion by activated group 2 innate lymphoid cells (ILC2s) to expand both goblet and tuft cells. We show that epithelial Elp3, a tRNA-modifying enzyme, promotes tuft cell differentiation and is consequently critical for IL-25 production, ILC2 activation, goblet cell expansion and control of Nippostrongylus brasiliensis helminth infection in mice. Elp3 is essential for the generation of intestinal immature tuft cells and for the IL-13-dependent induction of glycolytic enzymes such as Hexokinase 1 and Aldolase A. Importantly, loss of epithelial Elp3 in the intestine blocks the codon-dependent translation of the Gator1 subunit Nprl2, an mTORC1 inhibitor, which consequently enhances mTORC1 activation and stabilizes Atf4 in progenitor cells. Likewise, Atf4 overexpression in mouse intestinal epithelium blocks tuft cell differentiation in response to intestinal helminth infection. Collectively, our data define Atf4 as a negative regulator of tuft cells and provide insights into promotion of intestinal type 2 immune response to parasites through tRNA modifications.


Asunto(s)
Factor de Transcripción Activador 4 , Diferenciación Celular , Mucosa Intestinal , Diana Mecanicista del Complejo 1 de la Rapamicina , Animales , Ratones , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/parasitología , Mucosa Intestinal/inmunología , Mucosa Intestinal/citología , Nippostrongylus/inmunología , Células Caliciformes/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Interleucina-13/metabolismo , Interleucina-13/genética
4.
EMBO J ; 41(18): e109353, 2022 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-35920020

RESUMEN

Macrophage polarization is a process whereby macrophages acquire distinct effector states (M1 or M2) to carry out multiple and sometimes opposite functions. We show here that translational reprogramming occurs during macrophage polarization and that this relies on the Elongator complex subunit Elp3, an enzyme that modifies the wobble uridine base U34 in cytosolic tRNAs. Elp3 expression is downregulated by classical M1-activating signals in myeloid cells, where it limits the production of pro-inflammatory cytokines via FoxO1 phosphorylation, and attenuates experimental colitis in mice. In contrast, alternative M2-activating signals upregulate Elp3 expression through a PI3K- and STAT6-dependent signaling pathway. The metabolic reprogramming linked to M2 macrophage polarization relies on Elp3 and the translation of multiple candidates, including the mitochondrial ribosome large subunit proteins Mrpl3, Mrpl13, and Mrpl47. By promoting translation of its activator Ric8b in a codon-dependent manner, Elp3 also regulates mTORC2 activation. Elp3 expression in myeloid cells further promotes Wnt-driven tumor initiation in the intestine by maintaining a pool of tumor-associated macrophages exhibiting M2 features. Collectively, our data establish a functional link between tRNA modifications, mTORC2 activation, and macrophage polarization.


Asunto(s)
Histona Acetiltransferasas , Activación de Macrófagos , Transducción de Señal , Animales , Codón/metabolismo , Histona Acetiltransferasas/genética , Activación de Macrófagos/genética , Macrófagos/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/genética , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Ratones
5.
EMBO J ; 40(23): e109935, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34751964

RESUMEN

While key developmental functions of neurotransmitters have been described in rodent neural progenitors, there is a lack of understanding of their roles in the human fetal brain. A new study published in The EMBO Journal demonstrates that human cortical interneurons that are moving in fused brain organoids express a large repertoire of neurotransmitter receptors whose activation fine tunes selective migration strategies.


Asunto(s)
Interneuronas , Neurogénesis , Movimiento Celular , Humanos , Neurotransmisores , Organoides
6.
Nature ; 567(7746): 113-117, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30787442

RESUMEN

The expansion of brain size is accompanied by a relative enlargement of the subventricular zone during development. Epithelial-like neural stem cells divide in the ventricular zone at the ventricles of the embryonic brain, self-renew and generate basal progenitors1 that delaminate and settle in the subventricular zone in enlarged brain regions2. The length of time that cells stay in the subventricular zone is essential for controlling further amplification and fate determination. Here we show that the interphase centrosome protein AKNA has a key role in this process. AKNA localizes at the subdistal appendages of the mother centriole in specific subtypes of neural stem cells, and in almost all basal progenitors. This protein is necessary and sufficient to organize centrosomal microtubules, and promote their nucleation and growth. These features of AKNA are important for mediating the delamination process in the formation of the subventricular zone. Moreover, AKNA regulates the exit from the subventricular zone, which reveals the pivotal role of centrosomal microtubule organization in enabling cells to both enter and remain in the subventricular zone. The epithelial-to-mesenchymal transition is also regulated by AKNA in other epithelial cells, demonstrating its general importance for the control of cell delamination.


Asunto(s)
Centrosoma/metabolismo , Proteínas de Unión al ADN/metabolismo , Ventrículos Laterales/citología , Ventrículos Laterales/embriología , Microtúbulos/metabolismo , Neurogénesis , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Animales , Movimiento Celular , Células Cultivadas , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal , Humanos , Uniones Intercelulares/metabolismo , Interfase , Ventrículos Laterales/anatomía & histología , Glándulas Mamarias Animales/citología , Ratones , Tamaño de los Órganos , Organoides/citología
7.
Proc Natl Acad Sci U S A ; 119(46): e2209714119, 2022 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-36343267

RESUMEN

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.


Asunto(s)
Encefalopatías , Proteínas Represoras , Animales , Ratones , Proteínas Represoras/metabolismo , Cinesinas/genética , Microtúbulos/metabolismo , Neuronas/metabolismo , Encefalopatías/metabolismo
8.
Nat Rev Neurosci ; 20(6): 318-329, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30874623

RESUMEN

The cerebral cortex is an evolutionarily advanced brain structure that computes higher motor, sensory and cognitive functions. Its complex organization reflects the exquisite cell migration and differentiation patterns that take place during embryogenesis. Recent evidence supports an essential role for cell migration in shaping the developing cerebral cortex via direct cellular contacts and spatially organized diffusible cues that regulate the establishment of its cytoarchitecture and function. Identifying the nature of the crosstalk between cell populations at play during brain development is key to understanding how cerebral cortical morphogenesis proceeds in health and disease.


Asunto(s)
Comunicación Celular/fisiología , Movimiento Celular/fisiología , Corteza Cerebral/fisiología , Morfogénesis/fisiología , Neurogénesis/fisiología , Animales , Corteza Cerebral/citología , Humanos
9.
Brain ; 146(8): 3528-3541, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-36732302

RESUMEN

Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder with progressive congenital microcephaly and early death. SMPD4 encodes a sphingomyelinase that hydrolyses sphingomyelin into ceramide at neutral pH and can thereby affect membrane lipid homeostasis. SMPD4 localizes to the membranes of the endoplasmic reticulum and nuclear envelope and interacts with nuclear pore complexes (NPC). We refine the clinical phenotype of loss-of-function SMPD4 variants by describing five individuals from three unrelated families with longitudinal data due to prolonged survival. All individuals surviving beyond infancy developed insulin-dependent diabetes, besides presenting with a severe neurodevelopmental disorder and microcephaly, making diabetes one of the most frequent age-dependent non-cerebral abnormalities. We studied the function of SMPD4 at the cellular and organ levels. Knock-down of SMPD4 in human neural stem cells causes reduced proliferation rates and prolonged mitosis. Moreover, SMPD4 depletion results in abnormal nuclear envelope breakdown and reassembly during mitosis and decreased post-mitotic NPC insertion. Fibroblasts from affected individuals show deficient SMPD4-specific neutral sphingomyelinase activity, without changing (sub)cellular lipidome fractions, which suggests a local function of SMPD4 on the nuclear envelope. In embryonic mouse brain, knockdown of Smpd4 impairs cortical progenitor proliferation and induces premature differentiation by altering the balance between neurogenic and proliferative progenitor cell divisions. We hypothesize that, in individuals with SMPD4-related disease, nuclear envelope bending, which is needed to insert NPCs in the nuclear envelope, is impaired in the absence of SMPD4 and interferes with cerebral corticogenesis and survival of pancreatic beta cells.


Asunto(s)
Diabetes Mellitus , Microcefalia , Humanos , Animales , Ratones , Membrana Nuclear/química , Membrana Nuclear/metabolismo , Microcefalia/genética , Microcefalia/metabolismo , Esfingomielina Fosfodiesterasa/análisis , Esfingomielina Fosfodiesterasa/genética , Esfingomielina Fosfodiesterasa/metabolismo , Poro Nuclear/metabolismo , Mitosis , Diabetes Mellitus/metabolismo
10.
Cell ; 136(3): 551-64, 2009 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-19185337

RESUMEN

The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here, we report that the multisubunit histone acetyltransferase Elongator complex, which contributes to transcript elongation, also regulates the maturation of projection neurons. Indeed, silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons. Strikingly, neurons defective in Elongator show reduced levels of acetylated alpha-tubulin. Reduction of alpha-tubulin acetylation via expression of a nonacetylatable alpha-tubulin mutant leads to comparable defects in cortical neurons and suggests that alpha-tubulin is a target of Elp3. This is further supported by the demonstration that Elp3 promotes acetylation and counteracts HDAC6-mediated deacetylation of this substrate in vitro. Our results uncover alpha-tubulin as a target of the Elongator complex and suggest that a tight regulation of its acetylation underlies the maturation of cortical projection neurons.


Asunto(s)
Movimiento Celular , Corteza Cerebral/citología , Histona Acetiltransferasas/metabolismo , Neuronas/citología , Tubulina (Proteína)/metabolismo , Acetilación , Animales , Línea Celular , Células Cultivadas , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Femenino , Humanos , Ratones , Complejos Multienzimáticos/metabolismo , Neurogénesis
11.
Development ; 147(10)2020 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-32253238

RESUMEN

The transcription factor Zeb2 controls fate specification and subsequent differentiation and maturation of multiple cell types in various embryonic tissues. It binds many protein partners, including activated Smad proteins and the NuRD co-repressor complex. How Zeb2 subdomains support cell differentiation in various contexts has remained elusive. Here, we studied the role of Zeb2 and its domains in neurogenesis and neural differentiation in the young postnatal ventricular-subventricular zone (V-SVZ), in which neural stem cells generate olfactory bulb-destined interneurons. Conditional Zeb2 knockouts and separate acute loss- and gain-of-function approaches indicated that Zeb2 is essential for controlling apoptosis and neuronal differentiation of V-SVZ progenitors before and after birth, and we identified Sox6 as a potential downstream target gene of Zeb2. Zeb2 genetic inactivation impaired the differentiation potential of the V-SVZ niche in a cell-autonomous fashion. We also provide evidence that its normal function in the V-SVZ also involves non-autonomous mechanisms. Additionally, we demonstrate distinct roles for Zeb2 protein-binding domains, suggesting that Zeb2 partners co-determine neuronal output from the mouse V-SVZ in both quantitative and qualitative ways in early postnatal life.


Asunto(s)
Ventrículos Laterales/embriología , Ventrículos Laterales/crecimiento & desarrollo , Neurogénesis/genética , Bulbo Olfatorio/embriología , Bulbo Olfatorio/crecimiento & desarrollo , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/metabolismo , Animales , Apoptosis/genética , Movimiento Celular/genética , Proliferación Celular/genética , Técnicas de Inactivación de Genes , Interneuronas/metabolismo , Ventrículos Laterales/metabolismo , Ratones , Ratones Noqueados , Células-Madre Neurales/metabolismo , Bulbo Olfatorio/metabolismo , Factores de Transcripción SOXD/metabolismo , Transducción de Señal/inmunología , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética
12.
Glia ; 70(11): 2157-2168, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35809029

RESUMEN

Microglia, the resident macrophages of the central nervous system, are highly motile cells that support brain development, provision neuronal signaling, and protect brain cells against damage. Proper microglial functioning requires constant cell movement and morphological changes. Interestingly, the transient receptor potential vanilloid 4 (TRPV4) channel, a calcium-permeable channel, is involved in hypoosmotic morphological changes of retinal microglia and regulates temperature-dependent movement of microglial cells both in vitro and in vivo. Despite the broad functions of TRPV4 and the recent findings stating a role for TRPV4 in microglial movement, little is known about how TRPV4 modulates cytoskeletal remodeling to promote changes of microglial motility. Here we show that acute inhibition of TRPV4, but not its constitutive absence in the Trpv4 KO cells, affects the morphology and motility of microglia in vitro. Using high-end confocal imaging techniques, we show a decrease in actin-rich filopodia and tubulin dynamics upon acute inhibition of TRPV4 in vitro. Furthermore, using acute brain slices we demonstrate that Trpv4 knockout microglia display lower ramification complexity, slower process extension speed and consequently smaller surveyed area. We conclude that TRPV4 inhibition triggers a shift in cytoskeleton remodeling of microglia influencing their migration and morphology.


Asunto(s)
Canales Catiónicos TRPV , Canales de Potencial de Receptor Transitorio , Cationes , Citoesqueleto , Microglía/fisiología , Canales Catiónicos TRPV/genética
13.
Addict Biol ; 27(1): e13102, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34611982

RESUMEN

Adolescence is a developmental period characterized by significant changes in brain architecture and behaviour. The immaturity of the adolescent brain is associated with heightened vulnerability to exogenous agents, including alcohol. Alcohol is the most consumed drug among teenagers, and binge-drinking during adolescence is a major public health concern. Studies have suggested that adolescent alcohol exposure may interfere with the maturation of frontal brain regions and lead to long-lasting behavioural consequences. In this study, by using a slightly modified version of the Drinking in the Dark paradigm, adolescent C57Bl6 mice reach high blood alcohol concentration after voluntary binge-drinking. In order to assess short- and long-term consequences of adolescent alcohol exposure (AAE), a battery of behavioural tests was performed during late adolescence and during adulthood. We showed that AAE had no short-term effect on young mice behaviour but rather increased anxiety- and depressive-like behaviours, as well as alcohol consumption during adulthood. Moreover, alcohol binge-drinking during adolescence dramatically decreased recognition memory performances and behavioural flexibility in both adult males and females. Furthermore, we showed that voluntary consumption of alcohol during adolescence did not trigger any major activation of the innate immune system in the prefrontal cortex. Together, our data suggest that voluntary alcohol binge-drinking in adolescent mice induces a delayed appearance of behavioural impairments in adulthood.


Asunto(s)
Conducta del Adolescente/efectos de los fármacos , Consumo Excesivo de Bebidas Alcohólicas/patología , Corteza Prefrontal/efectos de los fármacos , Adolescente , Animales , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL
14.
J Pharmacokinet Pharmacodyn ; 49(3): 381-394, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35166967

RESUMEN

Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate (ADC), combining a humanized monoclonal antibody (IgG1) targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and a potent cytotoxic maytansinoid derivative, DM4, inhibiting microtubule assembly. SAR408701 is currently in clinical development for the treatment of advanced solid tumors expressing CEACAM5. It is administered intravenously as a conjugated antibody with an average Drug Antibody Ratio (DAR) of 3.8. During SAR408701 clinical development, four entities were measured in plasma: conjugated antibody (SAR408701), naked antibody (NAB), DM4 and its methylated metabolite (MeDM4), both being active. Average DAR and proportions of individual DAR species were also assessed in a subset of patients. An integrated and semi-mechanistic population pharmacokinetic model describing the time-course of all entities in plasma and DAR measurements has been developed. All DAR moieties were assumed to share the same drug disposition parameters, excepted for clearance which differed for DAR0 (i.e. NAB entity). The conversion of higher DAR to lower DAR resulted in a DAR-dependent ADC deconjugation and was represented as an irreversible first-order process. Each conjugated antibody was assumed to contribute to DM4 formation. All data were fitted simultaneously and the model developed was successful in describing the pharmacokinetic profile of each entity. Such a structural model could be translated to other ADCs and gives insight of mechanistic processes governing ADC disposition. This framework will further be expanded to evaluate covariates impact on SAR408701 pharmacokinetics and its derivatives, and thus can help identifying sources of pharmacokinetic variability and potential efficacy and safety pharmacokinetic drivers.


Asunto(s)
Antineoplásicos , Inmunoconjugados , Maitansina , Anticuerpos Monoclonales Humanizados/farmacocinética , Antineoplásicos/farmacocinética , Moléculas de Adhesión Celular , Humanos , Inmunoconjugados/farmacocinética , Maitansina/química , Maitansina/farmacocinética
15.
Int J Mol Sci ; 23(21)2022 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-36361546

RESUMEN

The interest in therapeutic monoclonal antibodies (mAbs) has continuously growing in several diseases. However, their pharmacokinetics (PK) is complex due to their target-mediated drug disposition (TMDD) profiles which can induce a non-linear PK. This point is particularly challenging during the pre-clinical and translational development of a new mAb. This article reviews and describes the existing PK modeling approaches used to translate the mAbs PK from animal to human for intravenous (IV) and subcutaneous (SC) administration routes. Several approaches are presented, from the most empirical models to full physiologically based pharmacokinetic (PBPK) models, with a focus on the population PK methods (compartmental and minimal PBPK models). They include the translational approaches for the linear part of the PK and the TMDD mechanism of mAbs. The objective of this article is to provide an up-to-date overview and future perspectives of the translational PK approaches for mAbs during a model-informed drug development (MIDD), since the field of PK modeling has gained recently significant interest for guiding mAbs drug development.


Asunto(s)
Anticuerpos Monoclonales , Antineoplásicos Inmunológicos , Animales , Humanos , Modelos Biológicos , Distribución Tisular , Inyecciones Subcutáneas
16.
Int J Mol Sci ; 23(18)2022 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-36142366

RESUMEN

p27kip1 is a multifunctional protein that promotes cell cycle exit by blocking the activity of cyclin/cyclin-dependent kinase complexes as well as migration and motility via signaling pathways that converge on the actin and microtubule cytoskeleton. Despite the broad characterization of p27kip1 function in neural cells, little is known about its relevance in microglia. Here, we studied the role of p27kip1 in microglia using a combination of in vitro and in situ approaches. While the loss of p27kip1 did not affect microglial density in the cerebral cortex, it altered their morphological complexity in situ. However, despite the presence of p27kip1 in microglial processes, as shown by immunofluorescence in cultured cells, loss of p27kip1 did not change microglial process motility and extension after applying laser-induced brain damage in cortical brain slices. Primary microglia lacking p27kip1 showed increased phagocytic uptake of synaptosomes, while a cell cycle dead variant negatively affected phagocytosis. These findings indicate that p27kip1 plays specific roles in microglia.


Asunto(s)
Proteínas de Ciclo Celular , Microglía , Actinas , Ciclo Celular/fisiología , Proteínas de Ciclo Celular/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Quinasas Ciclina-Dependientes/metabolismo , Ciclinas/metabolismo , Microglía/metabolismo
17.
EMBO Rep ; 20(9): e47097, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31321879

RESUMEN

Protein homeostasis is essential to cell function, and a compromised ability to reduce the load of misfolded and aggregated proteins is linked to numerous age-related diseases, including hearing loss. Here, we show that altered proteostasis consequent to Elongator complex deficiency also impacts the proper development of the cochlea and results in deafness. In the absence of the catalytic subunit Elp3, differentiating spiral ganglion neurons display large aggresome-like structures and undergo apoptosis before birth. The cochlear mechanosensory cells are able to survive proteostasis disruption but suffer defects in polarity and stereociliary bundle morphogenesis. We demonstrate that protein aggregates accumulate at the apical surface of hair cells, where they cause a local slowdown of microtubular trafficking, altering the distribution of intrinsic polarity proteins and affecting kinocilium position and length. Alleviation of protein misfolding using the chemical chaperone 4-phenylbutyric acid during embryonic development ameliorates hair cell polarity in Elp3-deficient animals. Our study highlights the importance of developmental proteostasis in the cochlea and unveils an unexpected link between proteome integrity and polarized organization of cellular components.


Asunto(s)
Cóclea/citología , Cóclea/metabolismo , Células Ciliadas Auditivas/citología , Células Ciliadas Auditivas/fisiología , Proteostasis/fisiología , Polaridad Celular/genética , Polaridad Celular/fisiología , Técnica del Anticuerpo Fluorescente , Células HEK293 , Células Ciliadas Auditivas/metabolismo , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Humanos , Hibridación in Situ , Microscopía Confocal , Microscopía Electrónica de Rastreo , Modelos Biológicos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Pliegue de Proteína , Proteostasis/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo
18.
Hum Mol Genet ; 27(2): 224-238, 2018 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-29077851

RESUMEN

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.


Asunto(s)
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)/metabolismo
19.
Hum Mol Genet ; 27(7): 1276-1289, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29415125

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder of which the progression is influenced by several disease-modifying factors. Here, we investigated ELP3, a subunit of the elongator complex that modifies tRNA wobble uridines, as one of such ALS disease modifiers. ELP3 attenuated the axonopathy of a mutant SOD1, as well as of a mutant C9orf72 ALS zebrafish model. Furthermore, the expression of ELP3 in the SOD1G93A mouse extended the survival and attenuated the denervation in this model. Depletion of ELP3 in vitro reduced the modified tRNA wobble uridine mcm5s2U and increased abundance of insoluble mutant SOD1, which was reverted by exogenous ELP3 expression. Interestingly, the expression of ELP3 in the motor cortex of ALS patients was reduced and correlated with mcm5s2U levels. Our results demonstrate that ELP3 is a modifier of ALS and suggest a link between tRNA modification and neurodegeneration.


Asunto(s)
Esclerosis Amiotrófica Lateral , Histona Acetiltransferasas , Corteza Motora/metabolismo , Proteínas del Tejido Nervioso , ARN de Transferencia , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Procesamiento Postranscripcional del ARN , ARN de Transferencia/genética , ARN de Transferencia/metabolismo , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Pez Cebra
20.
Pediatr Blood Cancer ; 67(10): e28603, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32706505

RESUMEN

BACKGROUND: Busulfan (Bu) is the cornerstone of conditioning regimens prior to hematopoietic stem cell transplantation, widely used in both adults and children for the treatment of malignant and nonmalignant diseases. Despite an intravenous formulation, interindividual variability (IIV) remains high and optimal exposure difficult to achieve, especially in neonates and infants. PROCEDURE: To ensure both efficacy and safety, we set up in 2005 an observational study designed for children not fully assessed during the drug registration procedure. From a large cohort of 540 patients, we developed a Bu population pharmacokinetic model based on body weight (BW) and maturation concepts to reduce IIV and optimize exposure. A new dosing nomogram was evaluated to better fit the population pharmacokinetic model. RESULTS: Bu clearance IIV was significantly decreased from 61.3% (covariate-free model) to 28.6% when combining BW and maturation function. Median Bu area under the curve (AUC) was 1179 µmol/L × min compared to 1025 with the EMA dosing nomogram for children <9 kg. The target AUC was reached for each BW strata, significantly increasing the percentages of patients achieving reaching the targeted AUC as compared to FDA schedule. CONCLUSION: This new model made it possible to propose a novel dosing nomogram that better considered children below 16 kg of BW and allowed better initial exposure as compared to existing dosing schedules. This nomogram, which would be easy to use to determine an optimal dosing schedule in daily practice, will need to be validated in clinical routine. Therapeutic drug monitoring remains strongly advisable for small children and those with specific diseases.


Asunto(s)
Busulfano/farmacocinética , Busulfano/uso terapéutico , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Modelos Estadísticos , Nomogramas , Acondicionamiento Pretrasplante , Terapia Combinada , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Femenino , Estudios de Seguimiento , Neoplasias Hematológicas/patología , Humanos , Lactante , Masculino , Agonistas Mieloablativos/farmacocinética , Agonistas Mieloablativos/uso terapéutico , Pronóstico , Distribución Tisular
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