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Purkinje neuron differentiation

Stephanie Zur Nedden, Rafaela Eith, Christoph Schwarzer, Lucia Zanetti, Hartwig Seitter, Friedrich Fresser, Alexandra Koschak, Angus Jm Cameron, Peter J Parker, Gottfried Baier, Gabriele Baier-Bitterlich
Increasing evidence suggests that synapse dysfunctions are a major determinant of several neurodevelopmental and neurodegenerative diseases. Here we identify protein kinase N1 (PKN1) as a novel key player in fine-tuning the balance between axonal outgrowth and presynaptic differentiation in the parallel fiber (PF)-forming cerebellar granule cells (Cgc). Postnatal Pkn1-/- animals showed a defective PF-Purkinje cell (PC) synapse formation. In vitro, Pkn1-/- Cgc exhibited deregulated axonal outgrowth, elevated AKT phosphorylation and higher levels of neuronal differentiation-2 (NeuroD2), a transcription factor preventing presynaptic maturation...
March 1, 2018: Journal of Clinical Investigation
Maria Sundberg, Ivan Tochitsky, David E Buchholz, Kellen Winden, Ville Kujala, Kush Kapur, Deniz Cataltepe, Daria Turner, Min-Joon Han, Clifford J Woolf, Mary E Hatten, Mustafa Sahin
Accumulating evidence suggests that cerebellar dysfunction early in life is associated with autism spectrum disorder (ASD), but the molecular mechanisms underlying the cerebellar deficits at the cellular level are unclear. Tuberous sclerosis complex (TSC) is a neurocutaneous disorder that often presents with ASD. Here, we developed a cerebellar Purkinje cell (PC) model of TSC with patient-derived human induced pluripotent stem cells (hiPSCs) to characterize the molecular mechanisms underlying cerebellar abnormalities in ASD and TSC...
February 15, 2018: Molecular Psychiatry
Yuki Ogawa, Kyoko Kakumoto, Tetsu Yoshida, Ken-Ichiro Kuwako, Taisuke Miyazaki, Junji Yamaguchi, Ayumu Konno, Junichi Hata, Yasuo Uchiyama, Hirokazu Hirai, Masahiko Watanabe, Robert B Darnell, Hideyuki Okano, Hirotaka James Okano
Neuronal Elav-like (nElavl or neuronal Hu) proteins are RNA-binding proteins that regulate RNA stability and alternative splicing, which are associated with axonal and synaptic structures. nElavl proteins promote the differentiation and maturation of neurons via their regulation of RNA. The functions of nElavl in mature neurons are not fully understood, although Elavl3 is highly expressed in the adult brain. Furthermore, possible associations between nElavl genes and several neurodegenerative diseases have been reported...
February 9, 2018: Scientific Reports
Lauren M Watson, Maggie M K Wong, Jane Vowles, Sally A Cowley, Esther B E Becker
The establishment of a reliable model for the study of Purkinje cells in vitro is of particular importance, given their central role in cerebellar function and pathology. Recent advances in induced pluripotent stem cell (iPSC) technology offer the opportunity to generate multiple neuronal subtypes for study in vitro. However, to date, only a handful of studies have generated Purkinje cells from human pluripotent stem cells, with most of these protocols proving challenging to reproduce. Here, we describe a simplified method for the reproducible generation of Purkinje cells from human iPSCs...
February 3, 2018: Cerebellum
Brittney L Gurda, Jessica H Bagel, Samantha J Fisher, Mark L Schultz, Andrew P Lieberman, Peter Hand, Charles H Vite, Gary P Swain
The feline model of Niemann-Pick disease, type C1 (NPC1) recapitulates the clinical, neuropathological, and biochemical abnormalities present in children with NPC1. The hallmarks of disease are the lysosomal storage of unesterified cholesterol and multiple sphingolipids in neurons, and the spatial and temporal distribution of Purkinje cell death. In feline NPC1 brain, microtubule-associated protein 1 light chain 3 (LC3) accumulations, indicating autophagosomes, were found within axons and presynaptic terminals...
January 13, 2018: Journal of Neuropathology and Experimental Neurology
Jason A Estep, Wenny Wong, Yiu-Cheung E Wong, Brian M Loui, Martin M Riccomagno
During mammalian cerebellar development, postnatal granule cell progenitors proliferate in the outer part of the External Granule Layer (EGL). Postmitotic granule progenitors migrate tangentially in the inner EGL before switching to migrate radially inward, past the Purkinje cell layer, to achieve their final position in the mature Granule Cell Layer (GCL). Here, we show that the RacGAP β-chimaerin is expressed by a small population of late-born, premigratory granule cells. β-chimaerin deficiency causes a subset of granule cells to become arrested in the EGL, where they differentiate and form ectopic neuronal clusters...
January 12, 2018: Scientific Reports
Li He, Kun Yu, Fanghui Lu, Jiajia Wang, Laiman N Wu, Chuntao Zhao, Qianmei Li, Xianyao Zhou, Hanmin Liu, Dezhi Mu, Mei Xin, Mengsheng Qiu, Q Richard Lu
Bergmann glia facilitate granule neuron migration during development and maintain the cerebellar organization and functional integrity. At present, molecular control of Bergmann glia specification from cerebellar radial glia is not fully understood. In this report, we show that Zeb2 (a.k.a. Sip1 or Zfhx1b), a Mowat-Wilson-syndrome-associated transcriptional regulator, is highly expressed in Bergmann glia, but hardly detectable in astrocytes in the cerebellum. The mice lacking Zeb2 in cerebellar radial glia exhibit severe deficits in Bergmann glia specification, and develop cerebellar cortical lamination dysgenesis and locomotion defects...
January 11, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Lena Wischhof, Simona Maida, Antonia Piazzesi, Anna Gioran, Kristina Barragan Sanz, Stephan Irsen, Marc Beyer, Joachim L Schultze, Martin J Dyer, Paolo Salomoni, Dan Ehninger, Pierluigi Nicotera, Daniele Bano
Chromatin remodelers have emerged as prominent regulators of epigenetic processes and potential drivers of various human pathologies. The multi-subunit chromatin-remodeling SWI/SNF complex determines gene expression programs and, consequently, contributes to the differentiation, maturation and plasticity of neurons. Here, we investigate the elusive biological function of Bcl7a and Bcl7b, two newly identified subunits of the SWI/SNF complex that are highly expressed throughout the brain. We generated ubiquitous and neuron-specific Bcl7a and Bcl7b single and double knockout mice...
December 6, 2017: Scientific Reports
Elizabeth Bautista, Natanael Zarco, Nicolás Aguirre-Pineda, Manuel Lara-Lozano, Paula Vergara, Juan Antonio González-Barrios, Raúl Aguilar-Roblero, José Segovia
Growth arrest-specific 1 (Gas1) is a pleiotropic protein that induces apoptosis of tumor cells and has important roles during development. Recently, the presence of two forms of Gas1 was reported: one attached to the cell membrane by a GPI anchor; and a soluble extracellular form shed by cells. Previously, we showed that Gas1 is expressed in different areas of the adult mouse CNS. Here, we report the levels of Gas1 mRNA protein in different regions and analyzed its expressions in glutamatergic, GABAergic, and dopaminergic neurons...
November 6, 2017: Cellular and Molecular Neurobiology
Beatriz Alvarez-Castelao, Christoph T Schanzenbächer, Cyril Hanus, Caspar Glock, Susanne Tom Dieck, Aline R Dörrbaum, Ina Bartnik, Belquis Nassim-Assir, Elena Ciirdaeva, Anke Mueller, Daniela C Dieterich, David A Tirrell, Julian D Langer, Erin M Schuman
Although advances in protein labeling methods have made it possible to measure the proteome of mixed cell populations, it has not been possible to isolate cell-type-specific proteomes in vivo. This is because the existing methods for metabolic protein labeling in vivo access all cell types. We report the development of a transgenic mouse line where Cre-recombinase-induced expression of a mutant methionyl-tRNA synthetase (L274G) enables the cell-type-specific labeling of nascent proteins with a non-canonical amino-acid and click chemistry...
December 2017: Nature Biotechnology
E Y Scott, K D Woolard, C J Finno, M C T Penedo, J D Murray
Cerebellar Abiotrophy (CA) is a neurodegenerative disease in Arabian horses affecting the cerebellum, more specifically the Purkinje neurons. Although CA occurs in several domestic species, CA in Arabian horses is unique in that a single nucleotide polymorphism (SNP) has been associated with the disease. Total RNA sequencing (RNA-seq) was performed on CA-affected horses to address the molecular mechanism underlying the disease. This research expands upon the RNA-seq work by measuring the impact of the CA-associated SNP on the candidate gene MutY homolog (MUTYH) and its regulation, isoform-specific expression and protein localization...
January 1, 2018: Brain Research
Pamela Valnegri, Ju Huang, Tomoko Yamada, Yue Yang, Luis A Mejia, Ha Y Cho, Anna Oldenborg, Azad Bonni
Although ubiquitin ligases have been implicated in autism, their roles and mechanisms in brain development remain incompletely understood. Here, we report that in vivo knockdown or conditional knockout of the autism-linked ubiquitin ligase RNF8 or associated ubiquitin-conjugating enzyme UBC13 in rodent cerebellar granule neurons robustly increases the number of parallel fiber presynaptic boutons and functional parallel fiber/Purkinje cell synapses. In contrast to the role of nuclear RNF8 in proliferating cells, RNF8 operates in the cytoplasm in neurons to suppress synapse differentiation in vivo...
November 2, 2017: Nature Communications
Zhilai Yang, Na Chen, Rongjing Ge, Hao Qian, Jin-Hui Wang
A neuron sprouts an axon, and its branches to innervate many target neurons that are divergent in their functions. In order to efficiently regulate the diversified cells, the axon branches should differentiate functionally to be compatible with their target neurons, i.e., a function compatibility between presynaptic and postsynaptic partners. We have examined this hypothesis by using electrophysiological method in the cerebellum, in which the main axon of Purkinje cell projected to deep nucleus cells and the recurrent axons innervated the adjacent Purkinje cells...
September 22, 2017: Oncotarget
Nathalie Doorenweerd, Ahmed Mahfouz, Maaike van Putten, Rajaram Kaliyaperumal, Peter A C T' Hoen, Jos G M Hendriksen, Annemieke M Aartsma-Rus, Jan J G M Verschuuren, Erik H Niks, Marcel J T Reinders, Hermien E Kan, Boudewijn P F Lelieveldt
Duchenne muscular dystrophy (DMD) is a muscular dystrophy with high incidence of learning and behavioural problems and is associated with neurodevelopmental disorders. To gain more insights into the role of dystrophin in this cognitive phenotype, we performed a comprehensive analysis of the expression patterns of dystrophin isoforms across human brain development, using unique transcriptomic data from Allen Human Brain and BrainSpan atlases. Dystrophin isoforms show large changes in expression through life with pronounced differences between the foetal and adult human brain...
October 3, 2017: Scientific Reports
Norliyana Zainolabidin, Sandhya P Kamath, Ayesha R Thanawalla, Albert I Chen
GABAergic inhibitory neurons in the cerebellum are subdivided into Purkinje cells and distinct subtypes of interneurons from the same pool of progenitors, but the determinants of this diversification process are not well defined. To explore the transcriptional regulation of the development of cerebellar inhibitory neurons, we examined the role of Tfap2A and Tfap2B in the specification of GABAergic neuronal subtypes in mice. We show that Tfap2A and Tfap2B are expressed in inhibitory precursors during embryonic development and that their expression persists into adulthood...
2017: Frontiers in Molecular Neuroscience
Filippo Casoni, Laura Croci, Camilla Bosone, Roberta D'Ambrosio, Aurora Badaloni, Davide Gaudesi, Valeria Barili, Justyna R Sarna, Lino Tessarollo, Ottavio Cremona, Richard Hawkes, Søren Warming, G Giacomo Consalez
The Zfp423/ZNF423 gene encodes a 30-zinc-finger transcription factor involved in key developmental pathways. Although null Zfp423 mutants develop cerebellar malformations, the underlying mechanism remains unknown. ZNF423 mutations are associated with Joubert Syndrome, a ciliopathy causing cerebellar vermis hypoplasia and ataxia. ZNF423 participates in the DNA-damage response (DDR), raising questions regarding its role as a regulator of neural progenitor cell cycle progression in cerebellar development. To characterize in vivo the function of ZFP423 in neurogenesis, we analyzed allelic murine mutants in which distinct functional domains are deleted...
October 15, 2017: Development
Chuan Qin, Shan-Qiu Wu, Bao-Sheng Chen, Xiao-Xian Wu, Kun-Yao Qu, Jun-Min Liu, Gui-Fang Zhang, Yan-Feng Xu, Shunli Shu, Lihua Sun, Yan-Yong Li, Hua Zhu, Lan Huang, Chun-Mei Ma, Yu-Huan Xu, Yun-Lin Han, Yao-Zeng Lu
Objective To explore the efficacy of ganoderma lucidum preparation(Ling Zhi) in treating APP/PS-1 transgenic mouse models of Alzheimer's disease(AD).Methods APP/PS-1 transgenic mice of 4 months were randomly divided into model group,ganoderma lucidum treatment groups,including high [2250 mg/(kg·d)] and middle [750 mg/(kg·d)] dose groups,i.e.LZ-H and LZ-M groups,and the positive control group(treated with donepezil hydrochloride [2 mg/(kg·d)]).In addition,C57BL/6J wild mice were selected as normal group.The animals were administered for 4 months...
August 20, 2017: Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae
Gustavo A Higuera, Grazia Iaffaldano, Meiwand Bedar, Guy Shpak, Robin Broersen, Shashini T Munshi, Catherine Dupont, Joost Gribnau, Femke M S de Vrij, Steven A Kushner, Chris I De Zeeuw
The directed differentiation of patient-derived induced pluripotent stem cells into cell-type specific neurons has inspired the development of therapeutic discovery for neurodegenerative diseases. Many forms of ataxia result from degeneration of cerebellar Purkinje cells, but thus far it has not been possible to efficiently generate Purkinje neuron (PN) progenitors from human or mouse pluripotent stem cells, let alone to develop a methodology for in vivo transplantation in the adult cerebellum. Here, we present a protocol to obtain an expandable population of cerebellar neuron progenitors from mouse embryonic stem cells...
August 18, 2017: Scientific Reports
Masahiko Tanaka, Tomomi Senda, Naohide Hirashima
Cerebellar Purkinje cells differentiate the most elaborate dendritic trees among neurons in the brain and constitute the principal part of cerebellar neuronal circuitry. In the present study, we examined the role of the GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors in the dendritic differentiation of Purkinje cells. Since mature Purkinje cells express the GluA2 subunit, AMPA receptors on them exhibit a low Ca(2+) permeability. Does this expression of GluA2, leading to the loss of Ca(2+) permeability of AMPA receptors, have a positive significance in the dendritic differentiation of Purkinje cells? To answer this question, we introduced GluA2 siRNA into immature Purkinje cells in cerebellar cell cultures using a single-cell electroporation technique...
July 31, 2017: Neuroscience Letters
Qi Shi, Yingying Ge, Wanxia He, Xiangyou Hu, Riqiang Yan
Reticulon proteins (RTNs), consisting of RTN1 to RTN4, were previously shown to interact with BACE1 by negatively modulating its secretase activity. In RTN3-null mice, RTN1 expression was slightly elevated. To understand the in vivo role of RTN1, we generated RTN1-null mice and compared the effects of RTN1 and RTN3 on BACE1 modulation. We show that RTN1 is mostly expressed by neurons and not by glial cells under normal conditions, similar to the expression of RTN3. However, RTN1 is more localized in dendrites and is an excellent marker for dendrites of Purkinje cells, while RTN3 expression is less evident in dendrites...
July 21, 2017: Scientific Reports
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