Double Duty: Mitotic Kinesins and Their Post-Mitotic Functions in Neurons

Joseph, Naima T.; Swarnkar, Supriya; Puthanveettil, Sathyanarayanan V.

doi:10.3390/cells10010136

Cited by 11 publications

(4 citation statements)

References 73 publications

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“…Functional enrichment analysis of the set of upregulated genes demonstrated a significant enrichment of Gene Ontology (GO) categories associated with proliferation , cell cycle , and mitosis , likely reflecting the main compensatory mechanisms for aberrant neuronal development ( Figures 10B, C ; Supplementary Data 1 ). For example, upregulated genes encoding proteins are involved in cell cycle and mitosis regulation including Cdc20 , the coactivator of mitotic progression, which is also required for dendrite development ( 63 ); the transcription factor E2f1 , which is important for cell cycle progression and apoptosis ( 64 ); cyclin B1 ( Ccnb1 ) ( 65 ); Kif23 , which is important for cell division and implicated in neuronal migration ( 66 ); Cenpe , Cenpf , and Mki67 , which are important for cell cycle and mitosis ( 67 ); and Mcc , which is a regulator of cell cycle and Wnt/β-catenin signaling pathway ( 68 ). Additionally, we detected an elevated expression of glutamic acid decarboxylase 2 ( Gad2 ), the enzyme that catalyzes the formation of γ-aminobutyric acid (GABA) from glutamic acid.…”

Section: Resultsmentioning

confidence: 99%

Reprogramming of the developing heart by Hif1a-deficient sympathetic system and maternal diabetes exposure

Kolesova,

Hrabalova,

Bohuslavova

et al. 2024

Front. Endocrinol.

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IntroductionMaternal diabetes is a recognized risk factor for both short-term and long-term complications in offspring. Beyond the direct teratogenicity of maternal diabetes, the intrauterine environment can influence the offspring’s cardiovascular health. Abnormalities in the cardiac sympathetic system are implicated in conditions such as sudden infant death syndrome, cardiac arrhythmic death, heart failure, and certain congenital heart defects in children from diabetic pregnancies. However, the mechanisms by which maternal diabetes affects the development of the cardiac sympathetic system and, consequently, heightens health risks and predisposes to cardiovascular disease remain poorly understood.Methods and resultsIn the mouse model, we performed a comprehensive analysis of the combined impact of a Hif1a-deficient sympathetic system and the maternal diabetes environment on both heart development and the formation of the cardiac sympathetic system. The synergic negative effect of exposure to maternal diabetes and Hif1a deficiency resulted in the most pronounced deficit in cardiac sympathetic innervation and the development of the adrenal medulla. Abnormalities in the cardiac sympathetic system were accompanied by a smaller heart, reduced ventricular wall thickness, and dilated subepicardial veins and coronary arteries in the myocardium, along with anomalies in the branching and connections of the main coronary arteries. Transcriptional profiling by RNA sequencing (RNA-seq) revealed significant transcriptome changes in Hif1a-deficient sympathetic neurons, primarily associated with cell cycle regulation, proliferation, and mitosis, explaining the shrinkage of the sympathetic neuron population. DiscussionOur data demonstrate that a failure to adequately activate the HIF-1α regulatory pathway, particularly in the context of maternal diabetes, may contribute to abnormalities in the cardiac sympathetic system. In conclusion, our findings indicate that the interplay between deficiencies in the cardiac sympathetic system and subtle structural alternations in the vasculature, microvasculature, and myocardium during heart development not only increases the risk of cardiovascular disease but also diminishes the adaptability to the stress associated with the transition to extrauterine life, thus increasing the risk of neonatal death.

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Section: Resultsmentioning

confidence: 99%

Reprogramming of the developing heart by Hif1a-deficient sympathetic system and maternal diabetes exposure

Kolesova,

Hrabalova,

Bohuslavova

et al. 2024

Front. Endocrinol.

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“…In addition to reaffirming their shared control of the Rab11 recycling pathway, our MS studies also provided great insight into the NRP's diverging influence on non-canonical α5 integrin traffic in ECs. For example, α5 integrin's interactions with 6 kinesin-family proteins (Kif22, Kif2c, Kif4, Kif23, Kifc1 and Kif2a) [55][56][57][58][59] , Sorting nexin 18 (Snx18) 60 , and Rab3GAP2, (which acts as a GAP for Rab3 61 and a guanine nucleotide exchange factor (GEF) for Rab18 62 ), were all found to be NRP1-specific. Conversely, α5 integrin's interactions with Rab13 63 , Golgin A4 (Golga4) and Golgi SNAP receptor complex 1 (Gosr1) 64 were identified as NRP2 dependent.…”

Section: Discussionmentioning

confidence: 99%

A proteomics approach to isolating neuropilin-dependent α5 integrin trafficking pathways: neuropilin 1 and 2 co-traffic α5 integrin through endosomal p120RasGAP to promote polarised fibronectin fibrillogenesis in endothelial cells

Benwell,

Johnson,

Taylor

et al. 2024

Commun Biol

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Integrin trafficking to and from membrane adhesions is a crucial mechanism that dictates many aspects of a cell’s behaviour, including motility, polarisation, and invasion. In endothelial cells (ECs), the intracellular traffic of α5 integrin is regulated by both neuropilin 1 (NRP1) and neuropilin 2 (NRP2), yet the redundancies in function between these co-receptors remain unclear. Moreover, the endocytic complexes that participate in NRP-directed traffic remain poorly annotated. Here we identify an important role for the GTPase-activating protein p120RasGAP in ECs, promoting the recycling of α5 integrin from early endosomes. Mechanistically, p120RasGAP enables transit of endocytosed α5 integrin-NRP1-NRP2 complexes to Rab11+ recycling endosomes, promoting cell polarisation and fibronectin (FN) fibrillogenesis. Silencing of both NRP receptors, or p120RasGAP, resulted in the accumulation of α5 integrin in early endosomes, a loss of α5 integrin from surface adhesions, and attenuated EC polarisation. Endothelial-specific deletion of both NRP1 and NRP2 in the postnatal retina recapitulated our in vitro findings, severely impairing FN fibrillogenesis and polarised sprouting. Our data assign an essential role for p120RasGAP during integrin traffic in ECs and support a hypothesis that NRP receptors co-traffic internalised cargoes. Importantly, we utilise comparative proteomics analyses to isolate a comprehensive map of NRP1-dependent and NRP2-dependent α5 integrin interactions in ECs.

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“…In the nervous system, members of Kif family are localized in both mitotic and post-mitotic cells. In post-mitotic neurons, Kifs are essential motor proteins involved in neuronal migration, transport, and synaptic transmission (Joseph et al, 2021). Dysregulated expression of KIFs has been implicated in several neurological disorders, including amyotrophic lateral sclerosis, epilepsy, and Alzheimer’s disease (Asselin et al, 2020; Guillaud et al, 2020; Lucero et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Kinesin family member Kif23 regulates cytokinetic division and maintains neural stem/progenitor cell pool in the developing neocortex

Naher,

Kikkawa,

Iemura

et al. 2023

Preprint

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Accurate mitotic division of neural stem cell/progenitor cells (NSPCs) is crucial for the coordinated generation of progenitors and neurons in the developing cortex. Here, we investigated the pivotal role of Kif23, an N-kinesin motor protein, in embryonic mouse NSPCs. We found that Kif23 is highly expressed in the mitotic NSPCs within the embryonic cortex of both mouse and human. Knockdown (KD) of Kif23 led to precocious neurogenesis, attributed to an accelerated cell cycle exit, likely resulting from disrupted mitotic spindle orientation and impaired cytokinesis. Kif23 KD induced upregulation of the gamma-H2AX-p53-p21 signaling pathway, ultimately culminating in cytokinetic failure. Additionally, Kif23 depletion perturbed the apical surface structure of NSPCs and disrupted the proper localization of apical junctional proteins. Importantly, we demonstrated the successful rescue of Kif23 KD-induced phenotypes by introducing wild-type human KIF23, but not by a variant of KIF23 with a microcephaly-associated mutation. Our findings underscore the critical role of Kif23 in cortical development and provide novel insights into the intricate molecular mechanisms underlying pathogenesis of microcephaly.

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Double Duty: Mitotic Kinesins and Their Post-Mitotic Functions in Neurons

Cited by 11 publications

References 73 publications

Reprogramming of the developing heart by Hif1a-deficient sympathetic system and maternal diabetes exposure

Reprogramming of the developing heart by Hif1a-deficient sympathetic system and maternal diabetes exposure

A proteomics approach to isolating neuropilin-dependent α5 integrin trafficking pathways: neuropilin 1 and 2 co-traffic α5 integrin through endosomal p120RasGAP to promote polarised fibronectin fibrillogenesis in endothelial cells

Kinesin family member Kif23 regulates cytokinetic division and maintains neural stem/progenitor cell pool in the developing neocortex

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