Role of adherens junctions and apical-basal polarity of neural stem/progenitor cells in the pathogenesis of neurodevelopmental disorders: a novel perspective on congenital Zika syndrome

Bustamante, F.; Miró, María Paz; Velásquez, Zahady D.; Molina, Luis; Ehrenfeld, Pamela; Rivera, Francisco J.; Bátiz, Luis Federico

doi:10.1016/j.trsl.2019.02.014

Cited by 10 publications

(6 citation statements)

References 216 publications

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“…The highly apicobasally polarized morphology of apical RGs is a mandatory requirement for successful cortical development as it governs the mode of cell division, neuronal production, specification and migration, and the integrity of the ventricular wall. Adherens junctions (AJs), the sites of cadherin-mediated cell-cell adhesion, play an obligate role in the induction and maintenance of apical RG polarity and are thus pivotal determinants of progenitor function and the establishment of a functional neocortex (Stocker and Chenn, 2015;Bustamante et al, 2019). Throughout the developmental period AJs undergo constant remodeling as RGs divide, new progenitors re-establish adhesion and their progeny detach from the neuroepithelium.…”

Section: Introductionmentioning

confidence: 99%

Adherens Junctions: Guardians of Cortical Development

Veeraval

O′Leary

Cooper

2020

Front. Cell Dev. Biol.

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Apical radial glia comprise the pseudostratified neuroepithelium lining the embryonic lateral ventricles and give rise to the extensive repertoire of pyramidal neuronal subtypes of the neocortex. The establishment of a highly apicobasally polarized radial glial morphology is a mandatory prerequisite for cortical development as it governs neurogenesis, neural migration and the integrity of the ventricular wall. As in all epithelia, cadherin-based adherens junctions (AJs) play an obligate role in the maintenance of radial glial apicobasal polarity and neuroepithelial cohesion. In addition, the assembly of resilient AJs is critical to the integrity of the neuroepithelium which must resist the tensile forces arising from increasing CSF volume and other mechanical stresses associated with the expansion of the ventricles in the embryo and neonate. Junctional instability leads to the collapse of radial glial morphology, disruption of the ventricular surface and cortical lamination defects due to failed neuronal migration. The fidelity of cortical development is therefore dependent on AJ assembly and stability. Mutations in genes known to control radial glial junction formation are causative for a subset of inherited cortical malformations (neuronal heterotopias) as well as perinatal hydrocephalus, reinforcing the concept that radial glial junctions are pivotal determinants of successful corticogenesis. In this review we explore the key animal studies that have revealed important insights into the role of AJs in maintaining apical radial glial morphology and function, and as such, have provided a deeper understanding of the aberrant molecular and cellular processes contributing to debilitating cortical malformations. We highlight the reciprocal interactions between AJs and the epithelial polarity complexes that impose radial glial apicobasal polarity. We also discuss the critical molecular networks promoting AJ assembly in apical radial glia and emphasize the role of the actin cytoskeleton in the stabilization of cadherin adhesion -a crucial factor in buffering the mechanical forces exerted as a consequence of cortical expansion.

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Section: Introductionmentioning

confidence: 99%

Adherens Junctions: Guardians of Cortical Development

Veeraval

O′Leary

Cooper

2020

Front. Cell Dev. Biol.

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“…The metabolic activity and function of these neural cells are tightly regulated by many systemic and local factors, such as as HSPs, and can generate cancerous endothelial cells or metastasis, spreading glioma (17, 143). Given the importance of the sequential expression of HSPs in stressed BMECs and in the differentiation of NSCs/NPCs, it will be essential to show which HSPs contribute to functional neurons, astrocytes, or oligodendrocytes, capable of repairing lesions in the adult brain or of inducing cerebral angiogenesis (144). The answer to these questions will be beneficial for the implementation of new therapeutic concepts based on biomaterials and the use of HSPs in the treatment of cerebrovascular diseases, brain trauma, neurodegeneration, brain tumors, or neuroinfection (15, 145, 146).…”

Section: Discussionmentioning

confidence: 99%

Molecular chaperones in the brain endothelial barrier: neurotoxicity or neuroprotection?

Thüringer

Garrido

2019

The FASEB Journal

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Brain microvascular endothelial cells (BMECs) interact with astrocytes and pericytes to form the blood–brain barrier (BBB). Their compromised function alters the BBB integrity, which is associated with early events in the pathogenesis of cancer, neurodegenerative diseases, and epilepsy. Interestingly, these conditions also induce the expression of heat shock proteins (HSPs). Here we review the contribution of major HSP families to BMEC and BBB function. Although investigators mainly report protective effects of HSPs in brain, contrasted results were obtained in BMEC, which depend both on the HSP and on its location, intra‐ or extracellular. The therapeutic potential of HSPs must be scrupulously analyzed before targeting them in patients to reduce the progression of brain lesions and improve neurologic outcomes in the long term.—Thuringer, D., Garrido, C. Molecular chaperones in the brain endothelial barrier: neurotoxicity or neuroprotection? FASEB J. 33, 11629–11639 (2019). http://www.fasebj.org

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“…Radial glial cells (RGCs), also known as neural stem/progenitor cells (NSPCs), play critical roles in the formation of the central nervous system (CNS). They give rise to most neurons and macroglial cells, and function as railways for instructing neuronal radial migration ( Rakic, 1972 ; Bustamante et al, 2019 ). In rodents, most RGCs are located in the ventricular zone (VZ), extending short apical and long basal processes (4, 5).…”

Section: Introductionmentioning

confidence: 99%

“…The temporal and regional coordination between proliferation and differentiation of NSPCs during embryonic brain development depends on a delicate and regulated balance between extrinsic signals and intrinsic pathways ( Gotz and Huttner, 2005 ). Defects in this biological balance have been associated with primary alterations in the neurogenic process, leading to the onset and progression of various brain developmental disorders, including microcephaly, hydrocephalus, and epilepsy ( Rodriguez and Guerra, 2017 ; Yoon et al, 2017 ; Thodeson et al, 2018 ; Bustamante et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…NSPCs from hyh mice (hyh-NSPCs) displayed reduced levels of α-SNAP and increased levels of phosphorylated AMPKα (pAMPKα Thr172 ), which were associated with a reduction in their proliferative activity and a preferential Radial glial cells (RGCs), also known as neural stem/progenitor cells (NSPCs), play critical roles in the formation of the central nervous system (CNS). They give rise to most neurons and macroglial cells, and function as railways for instructing neuronal radial migration (Rakic, 1972;Bustamante et al, 2019). In rodents, most RGCs are located in the ventricular zone (VZ), extending short apical and long basal processes (4,5).…”

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confidence: 99%

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Alpha-SNAP (M105I) mutation promotes neuronal differentiation of neural stem/progenitor cells through overactivation of AMPK

Bustamante-Barrientos¹,

Méndez-Ruette

Molina

et al. 2023

Front. Cell Dev. Biol.

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Background: The M105I point mutation in α-SNAP (Soluble N-ethylmaleimide-sensitive factor attachment protein-alpha) leads in mice to a complex phenotype known as hyh (hydrocephalus with hop gait), characterized by cortical malformation and hydrocephalus, among other neuropathological features. Studies performed by our laboratory and others support that the hyh phenotype is triggered by a primary alteration in embryonic neural stem/progenitor cells (NSPCs) that leads to a disruption of the ventricular and subventricular zones (VZ/SVZ) during the neurogenic period. Besides the canonical role of α-SNAP in SNARE-mediated intracellular membrane fusion dynamics, it also negatively modulates AMP-activated protein kinase (AMPK) activity. AMPK is a conserved metabolic sensor associated with the proliferation/differentiation balance in NSPCs.Methods: Brain samples from hyh mutant mice (hydrocephalus with hop gait) (B6C3Fe-a/a-Napahyh/J) were analyzed by light microscopy, immunofluorescence, and Western blot at different developmental stages. In addition, NSPCs derived from WT and hyh mutant mice were cultured as neurospheres for in vitro characterization and pharmacological assays. BrdU labeling was used to assess proliferative activity in situ and in vitro. Pharmacological modulation of AMPK was performed using Compound C (AMPK inhibitor) and AICAR (AMPK activator).Results: α-SNAP was preferentially expressed in the brain, showing variations in the levels of α-SNAP protein in different brain regions and developmental stages. NSPCs from hyh mice (hyh-NSPCs) displayed reduced levels of α-SNAP and increased levels of phosphorylated AMPKα (pAMPKαThr172), which were associated with a reduction in their proliferative activity and a preferential commitment with the neuronal lineage. Interestingly, pharmacological inhibition of AMPK in hyh-NSPCs increased proliferative activity and completely abolished the increased generation of neurons. Conversely, AICAR-mediated activation of AMPK in WT-NSPCs reduced proliferation and boosted neuronal differentiation.Discussion: Our findings support that α-SNAP regulates AMPK signaling in NSPCs, further modulating their neurogenic capacity. The naturally occurring M105I mutation of α-SNAP provokes an AMPK overactivation in NSPCs, thus connecting the α-SNAP/AMPK axis with the etiopathogenesis and neuropathology of the hyh phenotype.

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Role of adherens junctions and apical-basal polarity of neural stem/progenitor cells in the pathogenesis of neurodevelopmental disorders: a novel perspective on congenital Zika syndrome

Cited by 10 publications

References 216 publications

Adherens Junctions: Guardians of Cortical Development

Adherens Junctions: Guardians of Cortical Development

Molecular chaperones in the brain endothelial barrier: neurotoxicity or neuroprotection?

Alpha-SNAP (M105I) mutation promotes neuronal differentiation of neural stem/progenitor cells through overactivation of AMPK

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