Early ciliary and prominin-1 dysfunctions precede neurogenesis impairment in a mouse model of type 2 diabetes

Bachor, Tomás P.; Karbanová, Jana; Büttner, Edgar; Bermúdez, Vicente; Marquioni-Ramella, Melisa D.; Carmeliet, Peter; Corbeil, Denis; Suburo, Ángela M.

doi:10.1016/j.nbd.2017.07.010

Cited by 13 publications

(13 citation statements)

References 68 publications

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“…S1k-q). These data, together with the recently reported defects in ependymal cilia of diabetic mice, 4 suggest that ciliary defects are more widespread in diabetes than previously appreciated.…”

Section: Dear Editorsupporting

confidence: 63%

Ciliary defects caused by dysregulation of O-GlcNAc modification are associated with diabetic complications

Guo

et al. 2018

Cell Res

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Section: Dear Editorsupporting

confidence: 63%

Ciliary defects caused by dysregulation of O-GlcNAc modification are associated with diabetic complications

Guo

et al. 2018

Cell Res

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“…In the latter context, we noticed alterations in primary cilia of MDCK cells expressing prominin‐1.s1/s2 mutants, notably Y819/828F (K.T. and D.C., unpublished data) and the collapse of motile cilia in ependymal cells where cilium‐associated prominin‐1 is delocalized in a mouse model of type 2 diabetes …”

Section: Discussionmentioning

confidence: 91%

Prominin‐1 (CD133) modulates the architecture and dynamics of microvilli

Thamm

Šimaitė

Karbanová

et al. 2018

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Prominin‐1 is a cell surface biomarker that allows the identification of stem and cancer stem cells from different organs. It is also expressed in several differentiated epithelial and non‐epithelial cells. Irrespective of the cell type, prominin‐1 is associated with plasma membrane protrusions. Here, we investigate its impact on the architecture of membrane protrusions using microvilli of Madin‐Darby canine kidney cells as the main model. Our high‐resolution analysis revealed that upon the overexpression of prominin‐1 the number of microvilli and clusters of them increased. Microvilli with branched and/or knob‐like morphologies were observed and stimulated by mutations in the ganglioside‐binding site of prominin‐1. The altered phenotypes were caused by the interaction of prominin‐1 with phosphoinositide 3‐kinase and Arp2/3 complex. Mutation of tyrosine 828 of prominin‐1 impaired its phosphorylation and thereby inhibited the aforementioned interactions abolishing altered microvilli. This suggests that the interplay of prominin‐1‐ganglioside membrane complexes, phosphoinositide 3‐kinase and cytoskeleton components regulates microvillar architecture. Lastly, the expression of prominin‐1 and its mutants modified the structure of filopodia emerging from fibroblast‐like cells and silencing human prominin‐1 in primary hematopoietic stem cells resulted in the loss of uropod‐associated microvilli. Altogether, these findings strengthen the role of prominin‐1 as an organizer of cellular protrusions.

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“…In the SVZ, neural stem cells (NSCs) produce undifferentiated and proliferative doublecortin (DCX) + neuroblasts that migrate towards the MOB where they differentiate mainly into interneurons playing an important role in the neuroplasticity of the MOB [ 31 , 81 ]. While the detrimental effects of T2D on the NSCs in the SVZ have been recently shown [ 3 , 49 , 59 , 60 ], it remains to be determined whether neurogenesis in the MOB is affected by T2D.…”

Section: Introductionmentioning

confidence: 99%

Type 2 diabetes impairs odour detection, olfactory memory and olfactory neuroplasticity; effects partly reversed by the DPP-4 inhibitor Linagliptin

Lietzau

Davidsson

Östenson

et al. 2018

acta neuropathol commun

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Recent data suggest that olfactory deficits could represent an early marker and a pathogenic mechanism at the basis of cognitive decline in type 2 diabetes (T2D). However, research is needed to further characterize olfactory deficits in diabetes, their relation to cognitive decline and underlying mechanisms.The aim of this study was to determine whether T2D impairs odour detection, olfactory memory as well as neuroplasticity in two major brain areas responsible for olfaction and odour coding: the main olfactory bulb (MOB) and the piriform cortex (PC), respectively. Dipeptidyl peptidase-4 inhibitors (DPP-4i) are clinically used T2D drugs exerting also beneficial effects in the brain. Therefore, we aimed to determine whether DPP-4i could reverse the potentially detrimental effects of T2D on the olfactory system.Non-diabetic Wistar and T2D Goto-Kakizaki rats, untreated or treated for 16 weeks with the DPP-4i linagliptin, were employed. Odour detection and olfactory memory were assessed by using the block, the habituation-dishabituation and the buried pellet tests. We assessed neuroplasticity in the MOB by quantifying adult neurogenesis and GABAergic inhibitory interneurons positive for calbindin, parvalbumin and carletinin. In the PC, neuroplasticity was assessed by quantifying the same populations of interneurons and a newly identified form of olfactory neuroplasticity mediated by post-mitotic doublecortin (DCX) + immature neurons.We show that T2D dramatically reduced odour detection and olfactory memory. Moreover, T2D decreased neurogenesis in the MOB, impaired the differentiation of DCX+ immature neurons in the PC and altered GABAergic interneurons protein expression in both olfactory areas. DPP-4i did not improve odour detection and olfactory memory. However, it normalized T2D-induced effects on neuroplasticity.The results provide new knowledge on the detrimental effects of T2D on the olfactory system. This knowledge could constitute essentials for understanding the interplay between T2D and cognitive decline and for designing effective preventive therapies.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0517-1) contains supplementary material, which is available to authorized users.

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Early ciliary and prominin-1 dysfunctions precede neurogenesis impairment in a mouse model of type 2 diabetes

Cited by 13 publications

References 68 publications

Ciliary defects caused by dysregulation of O-GlcNAc modification are associated with diabetic complications

Ciliary defects caused by dysregulation of O-GlcNAc modification are associated with diabetic complications

Prominin‐1 (CD133) modulates the architecture and dynamics of microvilli

Type 2 diabetes impairs odour detection, olfactory memory and olfactory neuroplasticity; effects partly reversed by the DPP-4 inhibitor Linagliptin

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