scholarly journals BMP signalling is critical for maintaining homeostasis of hair follicles and intestine in adult mice

2017 ◽  
Author(s):  
Aditi Nag ◽  
Pallavi Nigam ◽  
Abhishek L. Narayanan ◽  
Megha Kumar ◽  
Ritika Ghosal ◽  
...  
Keyword(s):  
Cell Types ◽  
Hair Follicles ◽  
Intestinal Cell ◽  
Knock Out ◽  
Adult Mice ◽  
Rapid Changes ◽  
Anagen Hair ◽  
Mouse Intestine ◽  
Bmp Signalling

AbstractBMP signalling play critical roles during embryonic development, however, its roles have not been extensively studied in the maintenance of adult tissue homeostasis. In this study we have used temporal knock out of Bmp2 and Bmp4 to uncover the role of BMP signalling in adult mice. We observed rapid changes in the adult hair follicles and the intestine within two days of depleting BMP signalling, which demonstrates the critical and acute requirement of BMP signalling in maintaining homeostasis in these tissues. In addition, our study demonstrates that while BMP signalling is required for maintenance of quiescence in telogen hair follicles, it is needed for survival and proliferation in late anagen hair follicles. Our study also reveals differential requirement of BMP signalling in differentiation of distinct intestinal cell types. In addition, Loss of BMP signalling rapidly promotes early neoplastic transformations in mouse intestine.

scholarly journals Inhibition of mTOR during a postnatal critical sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss of TSC1

2020 ◽  
Author(s):  
Mayukh Choudhury ◽  
Clara A. Amegandjin ◽  
Vidya Jadhav ◽  
Josianne Nunes Carriço ◽  
Ariane Quintal ◽  
...  
Keyword(s):  
Social Behavior ◽  
Time Course ◽  
Cell Types ◽  
Developmental Time ◽  
Adult Mice ◽  
Mtorc1 Signaling ◽  
Pv Cell ◽  
Mechanistic Basis

ABSTRACTMutations in regulators of the Mechanistic Target Of Rapamycin Complex 1 (mTORC1), such as Tsc1/2, lead to neurodevelopmental disorders associated with autism, intellectual disabilities and epilepsy. Whereas the effects of mTORC1 signaling dysfunction within diverse cell types are likely critical for the onset of the diverse neurological symptoms associated with mutations in mTORC1 regulators, they are not well understood. In particular, the effects of mTORC1 dys-regulation in specific types of inhibitory interneurons are unclear.Here, we showed that Tsc1 haploinsufficiency in parvalbumin (PV)-positive GABAergic interneurons either in cortical organotypic cultures or in vivo caused a premature increase in their perisomatic innervations, followed by a striking loss in adult mice. This effects were accompanied by alterations of AMPK-dependent autophagy in pre-adolescent but not adult mice. PV cell-restricted Tsc1 mutant mice showed deficits in social behavior. Treatment with the mTOR inhibitor Rapamycin restricted to the third postnatal week was sufficient to permanently rescue deficits in both PV cell innervation and social behavior in adult conditional haploinsufficient mice. All together, these findings identify a novel role of Tsc1-mTORC1 signaling in the regulation of the developmental time course and maintenance of cortical PV cell connectivity and provide a mechanistic basis for the targeted rescue of autism-related behaviors in disorders associated with deregulated mTORC1 signaling.

scholarly journals RHBDL4 protects against endoplasmic reticulum stress by regulating the morphology and distribution of ER sheets

2021 ◽  
Author(s):  
Viorica Liebe Lastun ◽  
Matthew Freeman
Keyword(s):  
Cell Cycle ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Liver Steatosis ◽  
Physiological Role ◽  
Cell Types ◽  
Rhomboid Protease ◽  
Rapid Changes

In metazoans, the architecture of the endoplasmic reticulum (ER) differs between cell types, and undergoes major changes through the cell cycle and according to physiological needs. Although much is known about how the different ER morphologies are generated and maintained, especially the ER tubules, how context dependent changes in ER shape and distribution are regulated and the factors involved are less characterized. Here, we show that RHBDL4, an ER-resident rhomboid protease, modulates the shape and distribution of the ER, especially under conditions that require rapid changes in the ER sheet distribution, including ER stress. RHBDL4 interacts with CLIMP-63, a protein involved in ER sheet stabilisation, and with the cytoskeleton. Mice lacking RHBDL4 are sensitive to ER stress and develop liver steatosis, a phenotype associated with unresolved ER stress. Our data introduce a new physiological role of RHBDL4 and also imply that this function does not require its enzymatic activity.

Abstract 238: ABCA1 and HDL3 are Required to Modulate Smooth Muscle Cells Trandifferentiation in a Myocardin-miR143/145-dependent Process

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Silvia Castiglioni ◽  
Alessio Vettore ◽  
Lorenzo Arnaboldi ◽  
Laura Calabresi ◽  
Alberto Corsini ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Cell Types ◽  
Foam Cells ◽  
Knock Out ◽  
Phenotypic Changes ◽  
Basal Expression ◽  
Basal Expression Level

Cells of the artery wall may accumulate free cholesterol and cholesteryl esters becoming foam cells. Up to 50% of foam cells in human lesions originates from smooth muscle cells (SMCs). Arterial SMCs express the ATP binding cassette (ABC) transporter ABCA1 and, upon cholesterol loading, express macrophage markers and a phagocytic activity. To characterize the role of ABCA1 and HDL3 in this transdifferentiation process, we evaluated the phenotypic changes in SMCs isolated from wild type (WT) and ABCA1 knock out (KO) mice and how HDL3 affects these changes. Cholesterol loading causes the downregulation of the expression of SMC markers including ACTA2, alpha-tropomyosin and myosin heavy chain and increases the expression of macrophage-related genes such as CD68, Mac-2, SRB1, MMPs, ABCG1 and ABCA1. HDL3 treatment in WT cells is able to normalize the expression of ACTA2, while the expression of macrophage-related genes is reduced. On the contrary, the preventive effect of HDL3 is completely lost in ABCA1 KO cells. Interestingly, the presence of HDL3 does not differently affect neutral lipid accumulation in WT or ABCA1 KO cells but stimulates phospholipids removal only in WT cells. ApoAI addition does not reverse the phenotypic changes induced by cholesterol not only in KO but also in WT cells. Moreover, cholesterol loading reduces the expression of myocardin, the master SMC specific-transcriptional coactivator involved in SMC differentiation, by up to 55% (p<0.01 vs respective control) in both cell types. HDL3 normalizes myocardin levels in WT cells while it does not have any effect in ABCA1 KO cells. Similar results are obtained evaluating the levels of miR-143/145, which positively regulate myocardin. The basal expression level of KLF4, a myocardin repressor, is almost double in ABCA1 KO cells compared to WT. After cholesterol loading, KLF4 is slightly reduced in WT cells, while its expression is halved in ABCA1 KO cells. HDL3 restores KLF4 to basal levels in KO cells, but it further reduces them in WT cells. These results indicate that HDL3, modulating the miR143/145-myocardin axis in SMC, prevents the cholesterol-induced gene expression modification regardless of its cholesterol unloading capacity and the presence of ABCA1 is required.

scholarly journals BACE1 partial deletion induces synaptic plasticity deficit in adult mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sylvia Lombardo ◽  
Martina Chiacchiaretta ◽  
Andrew Tarr ◽  
WonHee Kim ◽  
Tingyi Cao ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Axonal Guidance ◽  
Knock Out ◽  
App Processing ◽  
Aged Mice ◽  
Adult Mice ◽  
Term Potentiation ◽  
Partial Depletion

AbstractBACE1 is the first enzyme involved in APP processing, thus it is a strong therapeutic target candidate for Alzheimer’s disease. The observation of deleterious phenotypes in BACE1 Knock-out (KO) mouse models (germline and conditional) raised some concerns on the safety and tolerability of BACE1 inhibition. Here, we have employed a tamoxifen inducible BACE1 conditional Knock-out (cKO) mouse model to achieve a controlled partial depletion of BACE1 in adult mice. Biochemical and behavioural characterization was performed at two time points: 4–5 months (young mice) and 12–13 months (aged mice). A ~50% to ~70% BACE1 protein reduction in hippocampus and cortex, respectively, induced a significant reduction of BACE1 substrates processing and decrease of Aβx-40 levels at both ages. Hippocampal axonal guidance and peripheral nerve myelination were not affected. Aged mice displayed a CA1 long-term potentiation (LTP) deficit that was not associated with memory impairment. Our findings indicate that numerous phenotypes observed in germline BACE1 KO reflect a fundamental role of BACE1 during development while other phenotypes, observed in adult cKO, may be absent when partially rather than completely deleting BACE1. However, we demonstrated that partial depletion of BACE1 still induces CA1 LTP impairment, supporting a role of BACE1 in synaptic plasticity in adulthood.

Targeted disruption of the homeobox transcription factor Nkx2-3 in mice results in postnatal lethality and abnormal development of small intestine and spleen

Development ◽  
1999 ◽  
Vol 126 (10) ◽  
pp. 2215-2225 ◽  
Author(s):  
O. Pabst ◽  
R. Zweigerdt ◽  
H.H. Arnold
Keyword(s):  
Transcription Factor ◽  
Small Intestine ◽  
Cell Lineage ◽  
Cell Types ◽  
Abnormal Development ◽  
Intestinal Cell ◽  
White Pulp ◽  
Morphological Alterations ◽  
Signalling Molecules ◽  
Adult Mice

The homeodomain transcription factor Nkx2-3 is expressed in gut mesenchyme and spleen of embryonic and adult mice. Targeted inactivation of the Nkx2-3 gene results in severe morphological alterations of both organs and early postnatal lethality in the majority of homozygous mutants. Villus formation in the small intestine appears considerably delayed in Nkx2-3(−)/- foetuses due to reduced proliferation of the epithelium, while massively increased growth of crypt cells ensues in surviving adult mutants. Interestingly, differentiated cell types of the intestinal epithelium are present in homozygous mutants, suggesting that Nkx2-3 is not required for their cell lineage allocation or migration-dependent differentiation. Hyperproliferation of the gut epithelium in adult mutants is associated with markedly reduced expression of BMP-2 and BMP-4, suggesting that these signalling molecules may be involved in mediating non-cell-autonomous control of intestinal cell growth. Spleens of Nkx2-3 mutants are generally smaller and contain drastically reduced numbers of lymphatic cells. The white pulp appears anatomically disorganized, possibly owing to a homing defect in the spleen parenchyme. Moreover, some of the Nkx2-3 mutants exhibit asplenia. Taken together these observations indicate that Nkx2-3 is essential for normal development and functions of the small intestine and spleen.

Activation of the Notch pathway in the hair cortex leads to aberrant differentiation of the adjacent hair-shaft layers

Development ◽  
2000 ◽  
Vol 127 (11) ◽  
pp. 2421-2432 ◽  
Author(s):  
M.H. Lin ◽  
C. Leimeister ◽  
M. Gessler ◽  
R. Kopan
Keyword(s):  
Transgenic Mice ◽  
Hair Follicle ◽  
Active Form ◽  
Notch Pathway ◽  
Dermal Papilla ◽  
Cell Types ◽  
Hair Shaft ◽  
Hair Follicles ◽  
Hair Cortex

Little is known about the mechanisms underlying the generation of various cell types in the hair follicle. To investigate the role of the Notch pathway in this process, transgenic mice were generated in which an active form of Notch1 (Notch(DeltaE)) was overexpressed under the control of the mouse hair keratin A1 (MHKA1) promoter. MHKA-Notch(DeltaE) is expressed only in one precursor cell type of the hair follicle, the cortex. Transgenic mice could be easily identified by the phenotypes of curly whiskers and wavy, sheen pelage hair. No effects of activated Notch on proliferation were detected in hair follicles of the transgenic mice. We find that activating Notch signaling in the cortex caused abnormal differentiation of the medulla and the cuticle, two neighboring cell types that did not express activated Notch. We demonstrate that these non-autonomous effects are likely caused by cell-cell interactions between keratinocytes within the hair follicle and that Notch may function in such interactions either by directing the differentiation of follicular cells or assisting cells in interpreting a gradient emanating from the dermal papilla.

scholarly journals The mitochondrial DNA genetic bottleneck: inheritance and beyond

2018 ◽  
Vol 62 (3) ◽  
pp. 225-234 ◽  
Author(s):  
Haixin Zhang ◽  
Stephen P. Burr ◽  
Patrick F. Chinnery
Keyword(s):  
Molecular Mechanisms ◽  
Cell Types ◽  
Genetic Bottleneck ◽  
Comprehensive Understanding ◽  
Mtdna Mutations ◽  
Rapid Changes ◽  
Selection For ◽  
Different Levels ◽  
Different Tissues

mtDNA is a multicopy genome. When mutations exist, they can affect a varying proportion of the mtDNA present within every cell (heteroplasmy). Heteroplasmic mtDNA mutations can be maternally inherited, but the proportion of mutated alleles differs markedly between offspring within one generation. This led to the genetic bottleneck hypothesis, explaining the rapid changes in allele frequency seen during transmission from one generation to the next. Although a physical reduction in mtDNA has been demonstrated in several species, a comprehensive understanding of the molecular mechanisms is yet to be revealed. Several questions remain, including the role of selection for and against specific alleles, whether all bottlenecks are the same, and precisely how the bottleneck is controlled during development. Although originally thought to be limited to the germline, there is evidence that bottlenecks exist in other cell types during development, perhaps explaining why different tissues in the same organism contain different levels of mutated mtDNA. Moreover, tissue-specific bottlenecks may occur throughout life in response to environmental influences, adding further complexity to the situation. Here we review key recent findings, and suggest ways forward that will hopefully advance our understanding of the role of mtDNA in human disease.

scholarly journals c-Myc Is Required for the Formation of Intestinal Crypts but Dispensable for Homeostasis of the Adult Intestinal Epithelium

2005 ◽  
Vol 25 (17) ◽  
pp. 7868-7878 ◽  
Author(s):  
Michael D. Bettess ◽  
Nicole Dubois ◽  
Mark J. Murphy ◽  
Christelle Dubey ◽  
Catherine Roger ◽  
...  
Keyword(s):  
Small Intestine ◽  
Intestinal Epithelium ◽  
Cell Types ◽  
Molecular Evidence ◽  
Normal Numbers ◽  
Normal Epithelium ◽  
Independent Manner ◽  
Adult Mice ◽  
Canonical Wnt

ABSTRACT In self-renewing tissues such as the skin epidermis and the bone marrow, Myc proteins control differentiation of stem cells and proliferation of progenitor cell types. In the epithelium of the small intestine, we show that c-Myc and N-Myc are expressed in a differential manner. Whereas c-Myc is expressed in the proliferating transient-amplifying compartment of the crypts, N-Myc is restricted to the differentiated villus epithelium and a single cell located near the crypt base. c-Myc has been implicated as a critical target of the canonical Wnt pathway, which is essential for formation and maintenance of the intestinal mucosa. To genetically assess the role of c-Myc during development and homeostasis of the mammalian intestine we induced deletion of the c-myc flox allele in the villi and intestinal stem cell-bearing crypts of juvenile and adult mice, via tamoxifen-induced activation of the CreERT2 recombinase, driven by the villin promoter. Absence of c-Myc activity in the juvenile mucosa at the onset of crypt morphogenesis leads to a failure to form normal numbers of crypts in the small intestine. However, all mice recover from this insult to form and maintain a normal epithelium in the absence of c-Myc activity and without apparent compensation by N-Myc or L-Myc. This study provides genetic and molecular evidence that proliferation and expansion of progenitors necessary to maintain the adult intestinal epithelium can unexpectedly occur in a Myc-independent manner.

scholarly journals Fast and efficient generation of knock-in human organoids using homology-independent CRISPR/Cas9 precision genome editing

2020 ◽  
Author(s):  
Benedetta Artegiani ◽  
Delilah Hendriks ◽  
Joep Beumer ◽  
Rutger Kok ◽  
Xuan Zheng ◽  
...  
Keyword(s):  
Genome Editing ◽  
Dna Sequences ◽  
Mitotic Spindle ◽  
Cell Types ◽  
Intestinal Cell ◽  
Precise Integration ◽  
Exogenous Dna ◽  
Knock Out ◽  
Homology Directed Repair ◽  
Efficient Generation

AbstractCRISPR/Cas9 technology has revolutionized genome editing and is applicable to the organoid field. However, precise integration of exogenous DNA sequences in human organoids awaits robust knock-in approaches. Here, we describe CRISPR/Cas9-mediated Homology-independent Organoid Transgenesis (CRISPR-HOT), which allows efficient generation of knock-in human organoids representing different tissues. CRISPR-HOT avoids extensive cloning and outperforms homology directed repair (HDR) in achieving precise integration of exogenous DNA sequences at desired loci, without the necessity to inactivate TP53 in untransformed cells, previously used to increase HDR-mediated knock-in. CRISPR-HOT was employed to fluorescently tag and visualize subcellular structural molecules and to generate reporter lines for rare intestinal cell types. A double reporter labelling the mitotic spindle by tagged tubulin and the cell membrane by tagged E-cadherin uncovered modes of human hepatocyte division. Combining tubulin tagging with TP53 knock-out revealed TP53 involvement in controlling hepatocyte ploidy and mitotic spindle fidelity. CRISPR-HOT simplifies genome editing in human organoids.

scholarly journals Chronic overexpression of neuropeptide Y in the skin is sufficient to induce inflammation and epidermal and dermal pathology

2021 ◽  
Author(s):  
Zoya T. Anderson ◽  
Joseph W. Palmer ◽  
Andrzej T. Slominski ◽  
Jennifer L. Proctor ◽  
Misgana I. Idris ◽  
...  
Keyword(s):  
Neuropeptide Y ◽  
Cell Types ◽  
Hair Follicles ◽  
Dermal Fibrosis ◽  
Skin Physiology ◽  
Melanocyte Stem Cells ◽  
Inflammatory Processes ◽  
Transcriptional Changes ◽  
The Central Nervous System

Abstract Neuropeptide Y (NPY) is a pleiotropic peptide produced in the central nervous system and peripheral organs. Despite conjectures that NPY may have a role in skin physiology and pathology, the effects of NPY in this organ remain poorly understood. We reported that a knock-in mouse with entopic NPY overexpression exhibits significantly elevated NPY in the skin, accompanied by premature and progressive hair graying secondary to depletion of melanocyte stem cells within hair follicles. However, the question remains as to whether NPY overexpression in the skin can induce non-melanocyte pathology. In this study, we employed this mouse to investigate the consequences of skin-specific overexpression of NPY. Our findings show that chronic NPY overexpression in the skin induces dermal fibrosis and epidermal hyperkeratosis. Additionally, NPY overexpression induces significant accumulation of macrophages and regulatory T cells in the dermis. RNA sequencing of whole skin from NPY-overexpressing mice further reveals NPY-mediated transcriptional changes consistent with inflammatory processes and inflammation-associated skin changes and highlights novel cell types involved in the NPY-mediated response in the skin. Together, these results provide long-awaited evidence of NPY’s involvement in skin pathology, providing a background for defining the precise role of NPY in the regulation of cutaneous homeostasis and disease.

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