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1.
A. Maroli.
THE HUMAN-RESTRICTED DUPLICATED FORM OF THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR, CHRFAM7A: TRANSCRIPTIONAL REGULATION, ROLE IN INFLAMMATION AND POTENTIAL PHARMACOLOGICAL IMPLICATIONS.
Degree: 2017, Università degli Studi di Milano
URL: http://hdl.handle.net/2434/489077 
► The α7 nicotine acetylcholine receptor (α7nAChR, CHRNA7) is a homo-pentameric ligand-gated ion channel widely expressed in the Central Nervous System (CNS). Recent evidence has demonstrated…
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▼ The α7 nicotine acetylcholine receptor (α7nAChR, CHRNA7) is a homo-pentameric ligand-gated ion channel widely expressed in the Central Nervous System (CNS). Recent evidence has demonstrated its expression also in non-neuronal tissues, including monocytes and macrophages, where it mediates the Cholinergic Anti-Inflammatory Pathway, a neuronal reflex providing the central control of systemic inflammation.
Recently, the human-restricted duplicated gene of the α7nAChR, called CHRFAM7A (α7dup) has been discovered. It is the product of the partial duplication and fusion of exon 5-10 of CHRNA7 gene with the novel exons D, C, B and A belonging to the FAM7A gene, of unknown function. The CHRFAM7A gene is expressed in human immune cells and in the CNS and is translated into two proteins, of 45 kDa and 36 kDa, which are the result of alternative splicing. The α7dup protein assembles with the α7 conventional subunits and exerts a dominant negative regulation on the α7nAChR function. The importance of the α7dup protein in the human inflammatory process has been confirmed by the demonstration of its responsiveness to pro-inflammatory stimuli: indeed, the Lipopolysaccharide (LPS) treatment of THP-1 monocytic cells and of human primary monocytes and macrophages down-regulates CHRFAM7A transcript and protein through a transcriptional mechanism reliant on the NF-κB transcription factor. Moreover, unpublished data demonstrated that LPS has the opposite effect on the α7 transcript in monocytes and macrophages, leading to CHRNA7 up-regulation.
In this study, we have investigated the transcriptional mechanisms leading to CHRFAM7A expression in the THP-1 monocytic cells and in neuroblastoma SH-SY5Y cells and we demonstrate that the CHRFAM7A gene is endowed with several complex transcriptional mechanisms leading to fine expression modulation, including the presence of alternative and tissue-specific Transcription Start Site (TSS), alternative splicing mechanism, tissue-specific transcriptional elements and intronic silencer elements. Moreover, we demonstrated that the CHRFAM7A down-regulation exerted by LPS involve the chromatin remodeling of CHRFAM7A promoter in THP-1 cells.
Increasing evidence has linked CHRNA7 expressional and functional dysregulation to several neurodegenerative disorders, including Alzheimer’s disease. The treatment with the acetylcholinesterase inhibitor Donepezil is effective in temporary ameliorating the cognitive symptoms of AD, by increasing the synaptic levels of ACh and counteracting the cholinergic loss, which is characteristic of AD. However, emerging findings sustained that Donepezil can exert its therapeutic effect also by modulating the immune response and potentiating the Cholinergic Anti-Inflammatory Pathway.
So far, the role of CHRFAM7A gene in AD pathogenesis or pharmacological response has not been elucidated. In the present study, we have investigated the expression profile of CHRNA7 and CHRFAM7A genes in human nervous and immune tissues obtained from AD patients, highlighting expressional…
Advisors/Committee Members: relatore: G. Pietrini, coordinatore: M. Locati, PIETRINI, GRAZIA, PIETRINI, GRAZIA, LOCATI, MASSIMO.
Subjects/Keywords: CHRFAM7A; CHRNA7; Inflammation; Alzheimer's disease; Settore BIO/14 - Farmacologia
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APA (6th Edition):
Maroli, A. (2017). THE HUMAN-RESTRICTED DUPLICATED FORM OF THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR, CHRFAM7A: TRANSCRIPTIONAL REGULATION, ROLE IN INFLAMMATION AND POTENTIAL PHARMACOLOGICAL IMPLICATIONS. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/489077
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Maroli, A.. “THE HUMAN-RESTRICTED DUPLICATED FORM OF THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR, CHRFAM7A: TRANSCRIPTIONAL REGULATION, ROLE IN INFLAMMATION AND POTENTIAL PHARMACOLOGICAL IMPLICATIONS.” 2017. Thesis, Università degli Studi di Milano. Accessed January 19, 2021.
http://hdl.handle.net/2434/489077.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Maroli, A.. “THE HUMAN-RESTRICTED DUPLICATED FORM OF THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR, CHRFAM7A: TRANSCRIPTIONAL REGULATION, ROLE IN INFLAMMATION AND POTENTIAL PHARMACOLOGICAL IMPLICATIONS.” 2017. Web. 19 Jan 2021.
Vancouver:
Maroli A. THE HUMAN-RESTRICTED DUPLICATED FORM OF THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR, CHRFAM7A: TRANSCRIPTIONAL REGULATION, ROLE IN INFLAMMATION AND POTENTIAL PHARMACOLOGICAL IMPLICATIONS. [Internet] [Thesis]. Università degli Studi di Milano; 2017. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/2434/489077.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Maroli A. THE HUMAN-RESTRICTED DUPLICATED FORM OF THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR, CHRFAM7A: TRANSCRIPTIONAL REGULATION, ROLE IN INFLAMMATION AND POTENTIAL PHARMACOLOGICAL IMPLICATIONS. [Thesis]. Università degli Studi di Milano; 2017. Available from: http://hdl.handle.net/2434/489077
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
2.
F. Pischedda.
THE IGLON FAMILY MEMBER NEGR1 PROMOTES NEURONAL ARBORIZATION AND MIGRATION VIA FGFR2.
Degree: 2016, Università degli Studi di Milano
URL: http://hdl.handle.net/2434/363912
► Negr1 is a member of IgLON adhesion protein family but its functions are largely unknown. In our previous work ((Pischedda et al. 2014), APPENDIX I)…
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▼ Negr1 is a member of IgLON adhesion protein family but its functions are largely unknown. In our previous work ((Pischedda et al. 2014), APPENDIX I) we identified Negr1 as a developmentally regulated synaptic protein. Thus we examined the consequences of Negr1 acute down regulation. Strikingly, we found that Negr1 ablation impairs neuronal maturation in vitro. In this project we demonstrated thanks to complementary biochemical and imaging approaches that Negr1 organizes trans-synaptic heterodimer and influences neurites outgrowth via MAPK signaling. In detail, we demonstrated that ectopic Negr1 is sufficient to improve neurite arborization and to rescue the morphological phenotype observed in Negr1 silenced cells. This function is dependent on the activation of MAPK pathway through tyrosine kinase receptors. In fact, we found that Negr1 physically and functionally interacts with FGFR2, modulates FGFR2 response to FGF and consequently influences MAPK pathway. FGFR2 pathway plays an important role during brain development. Not surprisingly, our investigation of the radial migration of newly generated cortical neurons revealed that Negr1- FGFR2 cross-talk controls cortical organization in vivo. Noteworthy, mutations in NEGR1 and FGFR2 genes have been recently identified as ASD candidates. Autism spectrum disorder (ASD) affects 0.9% of children and it is recognized as the most genetic of all developmental neuropsychiatric syndromes. Connectivity dysfunctions have been suggested as causative alterations in ASD. Given the functional, physical and genetic correlation among Negr1 and FGFR2 and the impact of Negr1 on neuron morphology and migration, Negr1-FGFR2 molecular cross talk might arise as a key mechanism during CNS development.
Advisors/Committee Members: Pietrini%22%29&pagesize-30">tutor: G.
Pietrini,
co-tutor: G.Piccoli,
PIETRINI, GRAZIA.
Subjects/Keywords: Negr1; adhesion; FGFR2; migration; ASD; Settore BIO/09 - Fisiologia
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APA ·
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APA (6th Edition):
Pischedda, F. (2016). THE IGLON FAMILY MEMBER NEGR1 PROMOTES NEURONAL ARBORIZATION AND MIGRATION VIA FGFR2. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/363912
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Pischedda, F.. “THE IGLON FAMILY MEMBER NEGR1 PROMOTES NEURONAL ARBORIZATION AND MIGRATION VIA FGFR2.” 2016. Thesis, Università degli Studi di Milano. Accessed January 19, 2021.
http://hdl.handle.net/2434/363912.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Pischedda, F.. “THE IGLON FAMILY MEMBER NEGR1 PROMOTES NEURONAL ARBORIZATION AND MIGRATION VIA FGFR2.” 2016. Web. 19 Jan 2021.
Vancouver:
Pischedda F. THE IGLON FAMILY MEMBER NEGR1 PROMOTES NEURONAL ARBORIZATION AND MIGRATION VIA FGFR2. [Internet] [Thesis]. Università degli Studi di Milano; 2016. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/2434/363912.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Pischedda F. THE IGLON FAMILY MEMBER NEGR1 PROMOTES NEURONAL ARBORIZATION AND MIGRATION VIA FGFR2. [Thesis]. Università degli Studi di Milano; 2016. Available from: http://hdl.handle.net/2434/363912
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
3.
A. Crespi.
THE NOVEL DESMOSOMAL PROTEIN POF1B IS ESSENTIAL FOR CELL-CELL ADHESION STRENGTH.
Degree: 2014, Università degli Studi di Milano
URL: http://hdl.handle.net/2434/232408
► POF1B is a candidate gene for premature ovarian failure (POF); it is mainly expressed in polarized epithelial tissues, but its function in these tissues and…
(more)
▼ POF1B is a candidate gene for premature ovarian failure (POF); it is mainly expressed in polarized epithelial tissues, but its function in these tissues and the relationship with the disorder are unknown. In polarized epithelial MDCK cells the human stably expressed POF1B showed a tight junction localization that was lost by the POF1B R329Q variant associated with POF. Although the apico-basal polarity markers and ultrastructure of the tight junctions were maintained in cells expressing the mutant, tight junction assembly, as well as the organization of the monolayer appeared altered. Moreover, cells expressing the POF1B R329Q variant showed defects in ciliogenesis and cystogenesis as a result of misorientation of primary cilia and mitotic division. All of these defects were explained by interference of the mutant with the content and organization of F-actin at the junctions. Subsequently, by means of morphological and biochemical criteria we documented that POF1B is actually a desmosome- associated protein. Both in Caco-2 human intestinal cells and in stratified HaCaT keratinocyte cell lines, indeed, endogenous POF1B colocalized with desmoplakin and plakophilin 2 at the desmosomal plaque and in cytoplasmic particles aligned along intermediate filaments. POF1B co-fractionated with desmosomes and intermediate filament components and showed properties characteristic of desmosomes (i.e. detergent insolubility and calcium independence). Furthermore, POF1B was required for desmosome assembly and function, as the stable downregulation of the protein in HaCaT cells caused a decrease in desmosome number and size, and these desmosomes had very weak electron dense plaques. Among the cell-cell adhesion structures, desmosomes are the most essential for mechanical coupling. The reduced capability of POF1B-silenced keratinocytes to respond to mechanical stress revealed the protein's crucial role in these junctions. Moreover, altered desmosomes in POF1B- downregulated keratinocytes were associated with altered cell proliferation and differentiation. The localization of POF1B in simple and stratified epithelia, as well as its relocation to desmosomes in human skin tumors, further indicated the protein's role in desmosome function, and suggested its involvement in human diseases associated with impairment of these junctions.
Advisors/Committee Members: tutor: G. Pietrini, coordinatore: A. Gianni, PIETRINI, GRAZIA, GIANNI, ALESSANDRO.
Subjects/Keywords: POF1B; desmosome; polarity; simple and stratified epithelia; Settore BIO/14 - Farmacologia
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APA ·
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Manager
APA (6th Edition):
Crespi, A. (2014). THE NOVEL DESMOSOMAL PROTEIN POF1B IS ESSENTIAL FOR CELL-CELL ADHESION STRENGTH. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/232408
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Crespi, A.. “THE NOVEL DESMOSOMAL PROTEIN POF1B IS ESSENTIAL FOR CELL-CELL ADHESION STRENGTH.” 2014. Thesis, Università degli Studi di Milano. Accessed January 19, 2021.
http://hdl.handle.net/2434/232408.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Crespi, A.. “THE NOVEL DESMOSOMAL PROTEIN POF1B IS ESSENTIAL FOR CELL-CELL ADHESION STRENGTH.” 2014. Web. 19 Jan 2021.
Vancouver:
Crespi A. THE NOVEL DESMOSOMAL PROTEIN POF1B IS ESSENTIAL FOR CELL-CELL ADHESION STRENGTH. [Internet] [Thesis]. Università degli Studi di Milano; 2014. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/2434/232408.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Crespi A. THE NOVEL DESMOSOMAL PROTEIN POF1B IS ESSENTIAL FOR CELL-CELL ADHESION STRENGTH. [Thesis]. Università degli Studi di Milano; 2014. Available from: http://hdl.handle.net/2434/232408
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
4.
I. Ferrari.
THE ROLE OF THE IRSP53-LIN7 COMPLEX IN CELL MEMBRANE DYNAMICS.
Degree: 2015, Università degli Studi di Milano
URL: http://hdl.handle.net/2434/250654
► The insulin receptor substrate protein of 53 kDa is a critical factor in determining neuronal polarisation, as it initiates membrane protrusions to form filopodia and…
(more)
▼ The insulin receptor substrate protein of 53 kDa is a critical factor in determining neuronal polarisation, as it initiates membrane protrusions to form filopodia and neurites by coupling membrane deformation with F-actin polymerization. With its C-terminal tail, IRSp53 can bind to PDZ domain containing proteins including LIN7, a small scaffold protein possessing a single L27 domain, necessary for membrane recruitment. Here, we investigated the role of the IRSp53-LIN7 complex in cellular mechanisms that heavily rely on membrane deformation, such as the formation of filopodia and neurites or mitochondrial fission.
Concerning the role of the IRSp53:LIN7 complex in filopodia and neurite induction, our findings indicate that the formation of actin-filled filopodia and neurites depends on motifs mediating IRSp53-LIN7 association and filopodia tip localisation. We further showed that co-expression of LIN7 with IRSp53 enhanced the formation of filopodia protrusions in neuronal NSC34 cells, while also preventing the appearance of actin-deficient protrusions induced by the overexpression of IRSp53 alone. The positive regulatory role of LIN7 in IRSp53-mediated extension of filopodia was further demonstrated by live-cell imaging experiments in neuronal N2A cells. Moreover, LIN7 silencing in N2A cells prevented the extension of filopodia and neurites, induced by either the ectopic expression of IRSp53 or serum starvation. Defective neuritogenesis could be rescued by the expression of RNAi-resistant full length LIN7 or chimeric L27-IRSp53, whereas the expression of full length IRSp53 or the LIN7ΔPDZ mutant lacking the domain for association with IRSp53 was unable to restore neuritogenesis in LIN7 silenced cells. Finally, LIN7 silencing prevented the recruitment of IRSp53 in Triton X-100 insoluble complexes, otherwise occurring in differentiated cells. Collectively, this first set of data identify in LIN7 a novel regulator of the filopodia- and neurites-promoting activity of IRSp53, whose role is to spatially restrict its activity to the plasma membrane for filopodia and neurite initiation, and to further promote the stabilisation of these actin–rich structures.
More recently, we tested the hypothesis of a role for the IRSp53-LIN7 complex in the modification of intracellular membranes. To this regard, we found that endogenous LIN7 and IRSp53 localized in punctuate structures along mitochondria, a fact that prompted us to further investigate the possible effects of modifications in the expression levels of IRSp53/LIN7 on mitochondrial morphology. Eukaryotic cells, in fact, strictly regulate the overall morphology of their mitochondrial network thanks to the existence of protein complexes able to control fission and fusion events. We found that, upon overexpression of LIN7 and/or IRSp53, mitochondria morphology was altered, with a significant increase in the percentage of cells showing a less interconnected mitochondrial network compared to GFP-transfected control cells, a phenotype that was blocked by co-expression of the K38A…
Advisors/Committee Members: coordinatore: M. Locati, tutor: G. Pietrini, PIETRINI, GRAZIA, LOCATI, MASSIMO.
Subjects/Keywords: IRSp53; LIN7; IRSp53-LIN7 complex; N2A cells; NSC34 cells; filopodia; neurites; tip complex; mitochondrial morphology; mitochondrial fission; mitochondria pre-constriction sites; Settore BIO/13 - Biologia Applicata
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APA ·
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Manager
APA (6th Edition):
Ferrari, I. (2015). THE ROLE OF THE IRSP53-LIN7 COMPLEX IN CELL MEMBRANE DYNAMICS. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/250654
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Ferrari, I.. “THE ROLE OF THE IRSP53-LIN7 COMPLEX IN CELL MEMBRANE DYNAMICS.” 2015. Thesis, Università degli Studi di Milano. Accessed January 19, 2021.
http://hdl.handle.net/2434/250654.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Ferrari, I.. “THE ROLE OF THE IRSP53-LIN7 COMPLEX IN CELL MEMBRANE DYNAMICS.” 2015. Web. 19 Jan 2021.
Vancouver:
Ferrari I. THE ROLE OF THE IRSP53-LIN7 COMPLEX IN CELL MEMBRANE DYNAMICS. [Internet] [Thesis]. Università degli Studi di Milano; 2015. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/2434/250654.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Ferrari I. THE ROLE OF THE IRSP53-LIN7 COMPLEX IN CELL MEMBRANE DYNAMICS. [Thesis]. Università degli Studi di Milano; 2015. Available from: http://hdl.handle.net/2434/250654
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
. 
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