scholarly journals Dido mutations trigger perinatal death and generate brain abnormalities and behavioral alterations in surviving adult mice

2015 ◽  
Vol 112 (15) ◽  
pp. 4803-4808 ◽  
Author(s):  
Ricardo Villares ◽  
Julio Gutiérrez ◽  
Agnes Fütterer ◽  
Varvara Trachana ◽  
Fernando Gutiérrez del Burgo ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Perinatal Death ◽  
Genetic Disorders ◽  
Mutant Mice ◽  
Histone Deacetylase 6 ◽  
Behavioral Alterations ◽  
Agenesis Of Corpus Callosum ◽  
Adult Mice ◽  
Brain Malformations ◽  
Perinatal Lethality

Nearly all vertebrate cells have a single cilium protruding from their surface. This threadlike organelle, once considered vestigial, is now seen as a pivotal element for detection of extracellular signals that trigger crucial morphogenetic pathways. We recently proposed a role for Dido3, the main product of the death inducer-obliterator (dido) gene, in histone deacetylase 6 delivery to the primary cilium [Sánchez de Diego A, et al. (2014) Nat Commun 5:3500]. Here we used mice that express truncated forms of Dido proteins to determine the link with cilium-associated disorders. We describe dido mutant mice with high incidence of perinatal lethality and distinct neurodevelopmental, morphogenetic, and metabolic alterations. The anatomical abnormalities were related to brain and orofacial development, consistent with the known roles of primary cilia in brain patterning, hydrocephalus incidence, and cleft palate. Mutant mice that reached adulthood showed reduced life expectancy, brain malformations including hippocampus hypoplasia and agenesis of corpus callosum, as well as neuromuscular and behavioral alterations. These mice can be considered a model for the study of ciliopathies and provide information for assessing diagnosis and therapy of genetic disorders linked to the deregulation of primary cilia.

scholarly journals Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Janani Gopalan ◽  
Mitchell H Omar ◽  
Ankita Roy ◽  
Nelly M Cruz ◽  
Jerome Falcone ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Genetic Disorders ◽  
Chronic Kidney Failure ◽  
Actin Dynamics ◽  
Histone Deacetylase 6 ◽  
Collecting Ducts ◽  
Cytoskeletal Dynamics ◽  
Anchoring Protein ◽  
On Chip ◽  
The Stability

Pathophysiological defects in water homeostasis can lead to renal failure. Likewise, common genetic disorders associated with abnormal cytoskeletal dynamics in the kidney collecting ducts and perturbed calcium and cAMP signaling in the ciliary compartment contribute to chronic kidney failure. We show that collecting ducts in mice lacking the A-Kinase anchoring protein AKAP220 exhibit enhanced development of primary cilia. Mechanistic studies reveal that AKAP220-associated protein phosphatase 1 (PP1) mediates this phenotype by promoting changes in the stability of histone deacetylase 6 (HDAC6) with concomitant defects in actin dynamics. This proceeds through a previously unrecognized adaptor function for PP1 as all ciliogenesis and cytoskeletal phenotypes are recapitulated in mIMCD3 knock-in cells expressing a phosphatase-targeting defective AKAP220-ΔPP1 mutant. Pharmacological blocking of local HDAC6 activity alters cilia development and reduces cystogenesis in kidney-on-chip and organoid models. These findings identify the AKAP220-PPI-HDAC6 pathway as a key effector in primary cilia development.

Recent advances in animal model experimentation in autism research

2013 ◽  
Vol 26 (5) ◽  
pp. 264-271 ◽  
Author(s):  
Mousumi Tania ◽  
Md. Asaduzzaman Khan ◽  
Kun Xia
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Human Condition ◽  
Behavioral Alterations ◽  
Important Place ◽  
Adult Mice ◽  
Recent Advances ◽  
Model Study ◽  
Disease Biology ◽  
Animal Model Study

ObjectiveAutism, a lifelong neuro-developmental disorder is a uniquely human condition. Animal models are not the perfect tools for the full understanding of human development and behavior, but they can be an important place to start. This review focused on the recent updates of animal model research in autism.MethodsWe have reviewed the publications over the last three decades, which are related to animal model study in autism.ResultsAnimal models are important because they allow researchers to study the underlying neurobiology in a way that is not possible in humans. Improving the availability of better animal models will help the field to increase the development of medicines that can relieve disabling symptoms. Results from the therapeutic approaches are encouraging remarkably, since some behavioral alterations could be reversed even when treatment was performed on adult mice. Finding an animal model system with similar behavioral tendencies as humans is thus vital for understanding the brain mechanisms, supporting social motivation and attention, and the manner in which these mechanisms break down in autism. The ongoing studies should therefore increase the understanding of the biological alterations associated with autism as well as the development of knowledge-based treatments therapy for those struggling with autism.ConclusionIn this review, we have presented recent advances in research based on animal models of autism, raising hope for understanding the disease biology for potential therapeutic intervention to improve the quality of life of autism individuals.

scholarly journals Mitochondrial DNA Toxicity in Forebrain Neurons Causes Apoptosis, Neurodegeneration, and Impaired Behavior

2010 ◽  
Vol 30 (6) ◽  
pp. 1357-1367 ◽  
Author(s):  
Knut H. Lauritzen ◽  
Olve Moldestad ◽  
Lars Eide ◽  
Harald Carlsen ◽  
Gaute Nesse ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Cognitive Abilities ◽  
Natural Aging ◽  
Base Substitution ◽  
Behavioral Alterations ◽  
Adult Mice ◽  
Progressive Loss ◽  
Forebrain Neurons ◽  
High Level

ABSTRACT Mitochondrial dysfunction underlying changes in neurodegenerative diseases is often associated with apoptosis and a progressive loss of neurons, and damage to the mitochondrial genome is proposed to be involved in such pathologies. In the present study we designed a mouse model that allows us to specifically induce mitochondrial DNA toxicity in the forebrain neurons of adult mice. This is achieved by CaMKIIα-regulated inducible expression of a mutated version of the mitochondrial UNG DNA repair enzyme (mutUNG1). This enzyme is capable of removing thymine from the mitochondrial genome. We demonstrate that a continual generation of apyrimidinic sites causes apoptosis and neuronal death. These defects are associated with behavioral alterations characterized by increased locomotor activity, impaired cognitive abilities, and lack of anxietylike responses. In summary, whereas mitochondrial base substitution and deletions previously have been shown to correlate with premature and natural aging, respectively, we show that a high level of apyrimidinic sites lead to mitochondrial DNA cytotoxicity, which causes apoptosis, followed by neurodegeneration.

scholarly journals Tissue-Resident Macrophages Promote Renal Cystic Disease

2019 ◽  
Vol 30 (10) ◽  
pp. 1841-1856 ◽  
Author(s):  
Kurt A. Zimmerman ◽  
Cheng J. Song ◽  
Zhang Li ◽  
Jeremie M. Lever ◽  
David K. Crossman ◽  
...  
Keyword(s):  
Renal Injury ◽  
Primary Cilia ◽  
Kinase Inhibitor ◽  
Renal Cyst ◽  
Cyst Formation ◽  
Mutant Mice ◽  
Cystic Disease ◽  
Renal Cystic Disease ◽  
Resident Macrophage ◽  
Membrane Bound

BackgroundMutations affecting cilia proteins have an established role in renal cyst formation. In mice, the rate of cystogenesis is influenced by the age at which cilia dysfunction occurs and whether the kidney has been injured. Disruption of cilia function before postnatal day 12–14 results in rapid cyst formation; however, cyst formation is slower when cilia dysfunction is induced after postnatal day 14. Rapid cyst formation can also be induced in conditional adult cilia mutant mice by introducing renal injury. Previous studies indicate that macrophages are involved in cyst formation, however the specific role and type of macrophages responsible has not been clarified.MethodsWe analyzed resident macrophage number and subtypes during postnatal renal maturation and after renal injury in control and conditional Ift88 cilia mutant mice. We also used a pharmacological inhibitor of resident macrophage proliferation and accumulation to determine the importance of these cells during rapid cyst formation.ResultsOur data show that renal resident macrophages undergo a phenotypic switch from R2b (CD11clo) to R2a (CD11chi) during postnatal renal maturation. The timing of this switch correlates with the period in which cyst formation transitions from rapid to slow following induction of cilia dysfunction. Renal injury induces the reaccumulation of juvenile-like R2b resident macrophages in cilia mutant mice and restores rapid cystogenesis. Loss of primary cilia in injured conditional Ift88 mice results in enhanced epithelial production of membrane-bound CSF1, a cytokine that promotes resident macrophage proliferation. Inhibiting CSF1/CSF1-receptor signaling with a CSF1R kinase inhibitor reduces resident macrophage proliferation, R2b resident macrophage accumulation, and renal cyst formation in two mouse models of cystic disease.ConclusionsThese data uncover an important pathogenic role for resident macrophages during rapid cyst progression.

scholarly journals Ciliopathy-Associated Protein Kinase ICK Requires Its Non-Catalytic Carboxyl-Terminal Domain for Regulation of Ciliogenesis

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 677 ◽  
Author(s):  
Yoon Seon Oh ◽  
Eric J. Wang ◽  
Casey D. Gailey ◽  
David L. Brautigan ◽  
Benjamin L. Allen ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Primary Cilia ◽  
Catalytic Domain ◽  
Intestinal Cell ◽  
Loss Of Function ◽  
Kinase Gene ◽  
Intrinsically Disordered ◽  
Terminal Domain ◽  
Perinatal Lethality ◽  
Carboxyl Terminal

Loss-of-function mutations in the human ICK (intestinal cell kinase) gene cause dysfunctional primary cilia and perinatal lethality which are associated with human ciliopathies. The enzyme that we herein call CAPK (ciliopathy-associated protein kinase) is a serine/threonine protein kinase that has a highly conserved MAPK-like N-terminal catalytic domain and an unstructured C-terminal domain (CTD) whose functions are completely unknown. In this study, we demonstrate that truncation of the CTD impairs the ability of CAPK to interact with and phosphorylate its substrate, kinesin family member 3A (KIF3A). We also find that deletion of the CTD of CAPK compromises both localization to the primary cilium and negative regulation of ciliogenesis. Thus, CAPK substrate recognition, ciliary targeting, and ciliary function depend on the non-catalytic CTD of the protein which is predicted to be intrinsically disordered.

Role of GATA-1 in Proliferation and Differentiation of Definitive Erythroid and Megakaryocytic Cells In Vivo

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 434-442 ◽  
Author(s):  
Satoru Takahashi ◽  
Takuya Komeno ◽  
Naruyoshi Suwabe ◽  
Keigyo Yoh ◽  
Osamu Nakajima ◽  
...  
Keyword(s):  
Es Cells ◽  
Early Adulthood ◽  
Mutant Mice ◽  
Selection Marker ◽  
Adult Mice ◽  
Proliferation And Differentiation ◽  
Neomycin Resistance ◽  
Definitive Hematopoiesis

To elucidate the contributions of GATA-1 to definitive hematopoiesis in vivo, we have examined adult mice that were rendered genetically defective in GATA-1 synthesis (Takahashi et al, J Biol Chem272:12611, 1997). Because the GATA-1 gene is located on the X chromosome, which is randomly inactivated in every cell, heterozygous females can bear either an active wild-type or mutant (referred to asGATA-1.05) GATA-1 allele, consequently leading to variable anemic severity. These heterozygous mutant mice usually developed normally, but they began to die after 5 months. These affected animals displayed marked splenomegaly, anemia, and thrombocytopenia. Proerythroblasts and megakaryocytes massively accumulated in the spleens of the heterozygotes, and we showed that the neomycin resistance gene (which is the positive selection marker in ES cells) was expressed profusely in the abnormally abundant cells generated in the GATA-1.05 mutant females. We also observed hematopoiesis outside of the bone marrow in the affected mutant mice. These data suggest that a small number of GATA-1.05 mutant hematopoietic progenitor cells begin to proliferate vigorously during early adulthood, but because the cells are unable to terminally differentiate, this leads to progenitor proliferation in the spleen and consequently death. Thus, GATA-1 plays important in vivo roles for directing definitive hematopoietic progenitors to differentiate along both the erythroid and megakaryocytic pathways. The GATA-1 heterozygous mutant mouse shows a phenotype that is analogous to human myelodysplastic syndrome and thus may serve as a useful model for this disorder.

scholarly journals IFT-A deficiency in juvenile mice impairs biliary development and exacerbates ADPKD liver disease

2020 ◽  
Author(s):  
Wei Wang ◽  
Tana S Pottorf ◽  
Henry H Wang ◽  
Ruochen Dong ◽  
Matthew A. Kavanaugh ◽  
...  
Keyword(s):  
Liver Disease ◽  
Notch Signaling ◽  
Primary Cilia ◽  
Intraflagellar Transport ◽  
Erk Signaling ◽  
Knock Out ◽  
Adult Mice ◽  
Autosomal Dominant Polycystic Kidney ◽  
Knock Out Mice ◽  
Cyst Lining

AbstractPolycystic liver disease (PLD) is characterized by the growth of numerous biliary cysts and presents in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD), causing significant morbidity. Interestingly, deletion of intraflagellar transport-B (IFT-B) genes in adult mouse models of ADPKD attenuates severity of PKD and PLD. Here we examine the role of deletion of IFT-A gene, Thm1, in PLD of juvenile and adult Pkd2 conditional knock-out mice. Perinatal deletion of Thm1 results in disorganized and expanded biliary regions, biliary fibrosis, shortened primary cilia on CK19+ biliary epithelial cells, and reduced Notch signaling. In contrast, perinatal deletion of Pkd2 causes PLD, with multiple CK19+ biliary epithelial cell-lined cysts, fibrosis, lengthened primary cilia, and increased Notch and ERK signaling. Perinatal deletion of Thm1 in Pkd2 conditional knock-out mice increased hepatomegaly and liver necrosis, indicating enhanced liver disease severity. In contrast to effects in the developing liver, deletion of Thm1 in adult mice, alone and together with Pkd2, did not cause a biliary phenotype nor affect Pkd2-mutant PLD, respectively. However, similar to juvenile PLD, Notch and ERK signaling were increased in adult Pkd2-mutant cyst-lining cholangiocytes. Taken together, Thm1 is required for biliary tract development, likely by enabling Notch signaling, and proper biliary development restricts PLD severity. Unlike IFT-B genes, Thm1 does not affect hepatic cystogenesis, suggesting divergent regulation of signaling and cystogenic processes in the liver by IFT-B and –A. Notably, increased Notch signaling in cyst-lining cholangiocytes may indicate that aberrant activation of this pathway promotes hepatic cystogenesis, presenting as a novel potential therapeutic target.

scholarly journals Mice with targeted disruption of Hoxb-1 fail to form the motor nucleus of the VIIth nerve

Development ◽  
1996 ◽  
Vol 122 (10) ◽  
pp. 3217-3228 ◽  
Author(s):  
J.M. Goddard ◽  
M. Rossel ◽  
N.R. Manley ◽  
M.R. Capecchi
Keyword(s):  
Animal Model ◽  
Facial Nerve ◽  
Mutant Mice ◽  
Clinical Profile ◽  
Human Diseases ◽  
Motor Nucleus ◽  
Moebius Syndrome ◽  
Targeted Disruption ◽  
Adult Mice ◽  
Motor Component

Mice were generated with targeted disruptions in the hoxb-1 gene. Two separate mutations were created: the first disrupts only the homeodomain and the second inactivates the first exon as well as the homeodomain. The phenotypes associated with these two mutant alleles are indistinguishable in surviving adult mice. The predominant defect in these mutant mice is a failure to form the somatic motor component of the VIIth (facial) nerve, possibly through a failure to specify these neurons. The phenotype of hoxb-1 mutant homozygotes closely resembles features of the clinical profile associated with humans suffering from Bell's Palsy or Moebius Syndrome. These animals should therefore provide a useful animal model for these human diseases.

scholarly journals Modeling and treating GRIN2A developmental and epileptic encephalopathy in mice

2019 ◽  
Author(s):  
Ariadna Amador ◽  
Christopher D. Bostick ◽  
Heather Olson ◽  
Jurrian Peters ◽  
Chad R. Camp ◽  
...  
Keyword(s):  
Time Course ◽  
Rare Variants ◽  
De Novo ◽  
Hippocampal Slices ◽  
Combined Treatment ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Mutant Mice ◽  
Adult Mice ◽  
Mutant Receptors

ABSTRACTNMDA receptors (NMDAR) play crucial roles in excitatory synaptic transmission. Rare variants of GRIN2A, which encodes the GluN2A NMDAR subunit, are associated with several intractable neurodevelopmental disorders, including developmental and epileptic encephalopathy (DEE). A de novo missense variant, p.Ser644Gly (c.1930A>G), was identified in a child with DEE, and Grin2a knockin mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibit altered hippocampal morphology at two weeks of age, and homozygotes exhibit lethal tonic-clonic seizures in the third week. Heterozygous adult mice display a variety of distinct features, including resistance to electrically induced partial seizures, as well as hyperactivity and repetitive and reduced anxiety behaviors. Multielectrode recordings of mutant neuronal networks reveal hyperexcitability and altered bursting and synchronicity. When expressed in heterologous cells, mutant receptors exhibit enhanced NMDAR agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. Consistent with these observations, NMDAR-mediated synaptic currents in hippocampal slices from mutant mice show a prolonged deactivation time course. Standard antiepileptic drug monotherapy was ineffective in the patient, but combined treatment of NMDAR antagonists with antiepileptic drugs substantially reduced the seizure burden albeit without appreciable developmental improvement. Chronic treatment of homozygous mutant mouse pups with NMDAR antagonists delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of modeling severe neurodevelopmental seizure disorders using multiple experimental modalities and suggest their extended utility in identifying and evaluating new therapies.

scholarly journals CEP55 promotes cilia disassembly through stabilizing Aurora A kinase

2021 ◽  
Vol 220 (2) ◽  
Author(s):  
Yu-Cheng Zhang ◽  
Yun-Feng Bai ◽  
Jin-Feng Yuan ◽  
Xiao-Lin Shen ◽  
Yu-Ling Xu ◽  
...  
Keyword(s):  
Cell Surface ◽  
Primary Cilia ◽  
Perinatal Death ◽  
Clinical Manifestations ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Mammalian Development ◽  
Polycystic Kidneys ◽  
And Control

Primary cilia protrude from the cell surface and have diverse roles during development and disease, which depends on the precise timing and control of cilia assembly and disassembly. Inactivation of assembly often causes cilia defects and underlies ciliopathy, while diseases caused by dysfunction in disassembly remain largely unknown. Here, we demonstrate that CEP55 functions as a cilia disassembly regulator to participate in ciliopathy. Cep55−/− mice display clinical manifestations of Meckel–Gruber syndrome, including perinatal death, polycystic kidneys, and abnormalities in the CNS. Interestingly, Cep55−/− mice exhibit an abnormal elongation of cilia on these tissues. Mechanistically, CEP55 promotes cilia disassembly by interacting with and stabilizing Aurora A kinase, which is achieved through facilitating the chaperonin CCT complex to Aurora A. In addition, CEP55 mutation in Meckel–Gruber syndrome causes the failure of cilia disassembly. Thus, our study establishes a cilia disassembly role for CEP55 in vivo, coupling defects in cilia disassembly to ciliopathy and further suggesting that proper cilia dynamics are critical for mammalian development.

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