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1.
Proc Natl Acad Sci U S A ; 120(4): e2209964120, 2023 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-36669111

RESUMEN

Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B, which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the Tmem161b null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify TMEM161B as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.


Asunto(s)
Hurones , Proteínas Hedgehog , Animales , Femenino , Humanos , Ratones , Embarazo , Sistema Nervioso Central/metabolismo , Cilios/genética , Cilios/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Ratones Noqueados , Transducción de Señal
2.
bioRxiv ; 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38915567

RESUMEN

The human cerebral cortex, pivotal for advanced cognitive functions, is composed of six distinct layers and dozens of functionally specialized areas1,2. The layers and areas are distinguished both molecularly, by diverse neuronal and glial cell subtypes, and structurally, through intricate spatial organization3,4. While single-cell transcriptomics studies have advanced molecular characterization of human cortical development, a critical gap exists due to the loss of spatial context during cell dissociation5,6,7,8. Here, we utilized multiplexed error-robust fluorescence in situ hybridization (MERFISH)9, augmented with deep-learning-based cell segmentation, to examine the molecular, cellular, and cytoarchitectural development of human fetal cortex with spatially resolved single-cell resolution. Our extensive spatial atlas, encompassing 16 million single cells, spans eight cortical areas across four time points in the second and third trimesters. We uncovered an early establishment of the six-layer structure, identifiable in the laminar distribution of excitatory neuronal subtypes by mid-gestation, long before the emergence of cytoarchitectural layers. Notably, while anterior-posterior gradients of neuronal subtypes were generally observed in most cortical areas, a striking exception was the sharp molecular border between primary (V1) and secondary visual cortices (V2) at gestational week 20. Here we discovered an abrupt binary shift in neuronal subtype specification at the earliest stages, challenging the notion that continuous morphogen gradients dictate mid-gestation cortical arealization6,10. Moreover, integrating single-nuclei RNA-sequencing and in situ whole transcriptomics revealed an early upregulation of synaptogenesis in V1-specific Layer 4 neurons, suggesting a role of synaptogenesis in this discrete border formation. Collectively, our findings underscore the crucial role of spatial relationships in determining the molecular specification of cortical layers and areas. This work not only provides a valuable resource for the field, but also establishes a spatially resolved single-cell analysis paradigm that paves the way for a comprehensive developmental atlas of the human brain.

3.
Dev Cell ; 57(20): 2381-2396.e13, 2022 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-36228617

RESUMEN

Kinesins are canonical molecular motors but can also function as modulators of intracellular signaling. KIF26A, an unconventional kinesin that lacks motor activity, inhibits growth-factor-receptor-bound protein 2 (GRB2)- and focal adhesion kinase (FAK)-dependent signal transduction, but its functions in the brain have not been characterized. We report a patient cohort with biallelic loss-of-function variants in KIF26A, exhibiting a spectrum of congenital brain malformations. In the developing brain, KIF26A is preferentially expressed during early- and mid-gestation in excitatory neurons. Combining mice and human iPSC-derived organoid models, we discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways. Our findings illustrate the pathogenesis of KIF26A loss-of-function variants and identify the surprising versatility of this non-motor kinesin.


Asunto(s)
Cinesinas , Neuronas , Humanos , Animales , Ratones , Cinesinas/genética , Neuronas/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Apoptosis , Encéfalo/metabolismo
4.
J Mol Graph Model ; 97: 107580, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32193088

RESUMEN

Influenza B virus has two distinct lineages (Victoria and Yamagata) and are associated with seasonal influenza epidemics that cause respiratory illness. Influenza B hemagglutinin (HA) is a major surface glycoprotein with the receptor-binding site (RBS) primarily involved in viral pathogenesis. Generally, influenza B exclusively infects the human population which would insinuate that the structural variability of the influenza B HA RBS rarely changes. However, to our knowledge, the potential impact of variations in the influenza B HA RBS structural variability was not fully elucidated. Throughout this study, we generated models from the transitioning (evolving viral lineage) 1998-2018 influenza B/Yamagata HA, verified the quality of each HA model, performed HA RBS structural variability measurements, superimposed varying HA models for comparison, and designed a phylogenetic tree network for further analyses. We found that measurements of the transitioning HA RBS structural variability were generally maintained and, similarly, measurements of the altered (years that differed from the evolving viral lineage, specifically 2003, 2007, 2017) HA RBS structural variability differed from the transitioning HA RBS. Moreover, we observed that the altered HA RBS structural variability favored the formation of a putative Y202-H191 hydrogen bond which we postulate may increase structural stability, thereby, allowing for a winter infection of the virus. Furthermore, we established that changes in HA RBS structural variability does not influence viral evolution, but putatively seasonal infection.


Asunto(s)
Gripe Humana , Sitios de Unión , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Hemaglutininas , Humanos , Filogenia , Estaciones del Año
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