Pregnancy-associated plasma protein-A2 (PAPP-A2) is a novel homolog of PAPP-A in the metzincin superfamily. However, compared with the accumulating data on PAPP-A, very little is known about PAPP-A2. ...In this study, we determined the tissue expression pattern of PAPP-A2 mRNA in wild-type (WT) mice and characterized the phenotype of mice with global PAPP-A2 deficiency. Tissues expressing PAPP-A2 in WT mice were more limited than those expressing PAPP-A. The highest PAPP-A2 mRNA expression was found in the placenta, with abundant expression in fetal, skeletal, and reproductive tissues. Heterozygous breeding produced the expected Mendelian distribution for the pappa2 gene and viable homozygous PAPP-A2 knockout (KO) mice that were normal size at birth. The most striking phenotype of the PAPP-A2 KO mouse was postnatal growth retardation. Male and female PAPP-A2 KO mice had 10 and 25–30% lower body weight, respectively, than WT littermates. Adult femur and body length were also reduced in PAPP-A2 KO mice, but without significant effects on bone mineral density. PAPP-A2 KO mice were fertile, but with compromised fecundity. PAPP-A expression was not altered to compensate for the loss of PAPP-A2 expression, and proteolysis of PAPP-A2's primary substrate, IGF-binding protein-5, was not altered in fibroblasts from PAPP-A2 KO embryos. In conclusion, tissue expression patterns and biological consequences of gene KO indicate distinct physiological roles for PAPP-A2 and PAPP-A in mice.
Abstract Mice deficient in pregnancy-associated plasma protein-A (PAPP-A), an IGF binding protein protease, have been shown to be resistant to experimentally induced atherosclerosis and diabetic ...nephropathy, and, in the laboratory environment, live 30–40% longer than wild-type littermates in association with delayed incidence and occurrence of age-related neoplasms and degenerative diseases. Objective PAPP-A is highly expressed in the cerebellum and hippocampus of the mouse brain. Therefore, the studies presented here were aimed at determining motor behavior, learning and retention in PAPP-A knock-out (KO) mice compared to wild-type (WT) littermates with age. Design Balance and coordination were assessed using an accelerating rotarod; learning and memory were assessed in a Stone T-maze. Results Time on the rotarod decreased with age but there was no significant difference between PAPP-A KO and WT mice at any of the testing ages. Latency to reach the goal box and number of errors committed in the Stone T-maze did not change with age and there were no significant differences between PAPP-A KO and WT mice. Conclusion Lack of PAPP-A in mice did not impact central regulation of coordination, learning or memory.
Abstract Context Insulin-like growth factor (IGF) signaling is essential for achieving optimal body size during fetal development, peak bone mass during puberty, and maximal fecundity in the ...reproductive period. IGF-II is considered the main fetal IGF, whereas IGF-I is more important postnatally. Pregnancy-associated plasma protein-A (PAPP-A) enhances local IGF signaling through cleavage of inhibitory IGF binding proteins. Conversely, inhibition of PAPP-A results in reduced local IGF action. Thus, PAPP-A knock-out (KO) mice are born as proportional dwarfs due to the dysregulation of IGF-II signaling during early embryogenesis that impacts body size. Relaxation of IgfII imprinting through mutation of a reciprocally imprinted downstream gene, H19 , which allowed transcription of IGF-II from the normally silent maternal allele, rescued the dwarf phenotype of PAPP-A KO mice. Objective To determine the effect of increased IGF-II expression on postnatal phenotypes of PAPP-A KO mice. Design Young adult wild-type (WT), PAPP-A KO, H19 mutant (ΔH19/WT) and ΔH19/PAPP-A KO mice were characterized for skeletal phenotype (peripheral quantitative computed tomography at the midshaft and distal metaphysis of the femur) and reproductive phenotype (time to first litter, time between litters, pups per litter). Results Serum IGF-II levels were significantly increased in ΔH19/WT and ΔH19/PAPP-A KO mice compared to WT and PAPP-A KO mice; serum IGF-I levels were not affected by H19 mutation. PAPP-A KO mice had reductions in cortical thickness and in cortical and trabecular area, bone mineral content and bone mineral density compared to WT mice. There were no significant differences between PAPP-A KO and ΔH19/PAPP-A KO mice in any of the bone parameters. PAPP-A KO crossed with (×) PAPP-A KO had a longer time until first litter, normal time between subsequent litters, and significantly reduced number of pups per litter compared to WT × WT. ΔH19/PAPP-A KO × ΔH19/PAPP-A KO had an even longer time to first litter, but also longer time between litters. This phenotype was associated with female ΔH19/PAPP-A KO mice. Furthermore, these ΔH19/PAPP-A KO mouse mothers failed to care for their pups. Conclusions An increase in IGF-II expression did not rescue the skeletal and reproductive deficiencies associated with reduced local IGF-I signaling in PAPP-A KO mice. In addition, the data suggest a potential new role for genomic imprinting at the IgfII / H19 locus affecting maternal behavior.
Summary
Insulin‐like growth factor (IGF) signaling is essential for achieving optimal body size during fetal development, whereas, in the adult, IGFs are associated with aging and age‐related ...diseases. However, it is unclear as to what extent lifespan is influenced by events that occur during development. Here, we provide direct evidence that the exceptional longevity of mice with altered IGF signaling is not linked to prenatal programming of body size. Mice null for pregnancy‐associated plasma protein‐A (PAPP‐A), an IGF‐binding protein proteinase that increases local IGF bioavailability, are 60–70% the size of their wild‐type littermates at birth and have extended median and maximum lifespan of 30–40%. In this study, PAPP‐A−/− mice whose body size was normalized during fetal development through disruption of IgfII imprinting did not lose their longevity advantage. Adult‐specific moderation of IGF signaling through PAPP‐A inhibition may present a unique opportunity to improve lifespan without affecting important aspects of early life physiology.
Abstract Context Insulin-like growth factor (IGF) signaling is essential for achieving optimal body size during fetal development, peak bone mass during puberty, and maximal fecundity in the ...reproductive period. IGF-II is considered the main fetal IGF, whereas IGF-I is more important postnatally. Pregnancy-associated plasma protein-A (PAPP-A) enhances local IGF signaling through cleavage of inhibitory IGF binding proteins. Conversely, inhibition of PAPP-A results in reduced local IGF action. Thus, PAPP-A knock-out (KO) mice are born as proportional dwarfs due to the dysregulation of IGF-II signaling during early embryogenesis that impacts body size. Relaxation of IgfII imprinting through mutation of a reciprocally imprinted downstream gene, H19 , which allowed transcription of IGF-II from the normally silent maternal allele, rescued the dwarf phenotype of PAPP-A KO mice. Objective To determine the effect of increased IGF-II expression on postnatal phenotypes of PAPP-A KO mice. Design Young adult wild-type (WT), PAPP-A KO, H19 mutant (ΔH19/WT) and ΔH19/PAPP-A KO mice were characterized for skeletal phenotype (peripheral quantitative computed tomography at the midshaft and distal metaphysis of the femur) and reproductive phenotype (time to first litter, time between litters, pups per litter). Results Serum IGF-II levels were significantly increased in ΔH19/WT and ΔH19/PAPP-A KO mice compared to WT and PAPP-A KO mice; serum IGF-I levels were not affected by H19 mutation. PAPP-A KO mice had reductions in cortical thickness and in cortical and trabecular area, bone mineral content and bone mineral density compared to WT mice. There were no significant differences between PAPP-A KO and ΔH19/PAPP-A KO mice in any of the bone parameters. PAPP-A KO crossed with (×) PAPP-A KO had a longer time until first litter, normal time between subsequent litters, and significantly reduced number of pups per litter compared to WT × WT. ΔH19/PAPP-A KO × ΔH19/PAPP-A KO had an even longer time to first litter, but also longer time between litters. This phenotype was associated with female ΔH19/PAPP-A KO mice. Furthermore, these ΔH19/PAPP-A KO mouse mothers failed to care for their pups. Conclusions An increase in IGF-II expression did not rescue the skeletal and reproductive deficiencies associated with reduced local IGF-I signaling in PAPP-A KO mice. In addition, the data suggest a potential new role for genomic imprinting at the IgfII / H19 locus affecting maternal behavior.
Abstract Context Insulin-like growth factor (IGF) signaling is essential for achieving optimal body size during fetal development, peak bone mass during puberty, and maximal fecundity in the ...reproductive period. IGF-II is considered the main fetal IGF, whereas IGF-I is more important postnatally. Pregnancy-associated plasma protein-A (PAPP-A) enhances local IGF signaling through cleavage of inhibitory IGF binding proteins. Conversely, inhibition of PAPP-A results in reduced local IGF action. Thus, PAPP-A knock-out (KO) mice are born as proportional dwarfs due to the dysregulation of IGF-II signaling during early embryogenesis that impacts body size. Relaxation of IgfII imprinting through mutation of a reciprocally imprinted downstream gene, H19 , which allowed transcription of IGF-II from the normally silent maternal allele, rescued the dwarf phenotype of PAPP-A KO mice. Objective To determine the effect of increased IGF-II expression on postnatal phenotypes of PAPP-A KO mice. Design Young adult wild-type (WT), PAPP-A KO, H19 mutant (ΔH19/WT) and ΔH19/PAPP-A KO mice were characterized for skeletal phenotype (peripheral quantitative computed tomography at the midshaft and distal metaphysis of the femur) and reproductive phenotype (time to first litter, time between litters, pups per litter). Results Serum IGF-II levels were significantly increased in ΔH19/WT and ΔH19/PAPP-A KO mice compared to WT and PAPP-A KO mice; serum IGF-I levels were not affected by H19 mutation. PAPP-A KO mice had reductions in cortical thickness and in cortical and trabecular area, bone mineral content and bone mineral density compared to WT mice. There were no significant differences between PAPP-A KO and ΔH19/PAPP-A KO mice in any of the bone parameters. PAPP-A KO crossed with (×) PAPP-A KO had a longer time until first litter, normal time between subsequent litters, and significantly reduced number of pups per litter compared to WT × WT. ΔH19/PAPP-A KO × ΔH19/PAPP-A KO had an even longer time to first litter, but also longer time between litters. This phenotype was associated with female ΔH19/PAPP-A KO mice. Furthermore, these ΔH19/PAPP-A KO mouse mothers failed to care for their pups. Conclusions An increase in IGF-II expression did not rescue the skeletal and reproductive deficiencies associated with reduced local IGF-I signaling in PAPP-A KO mice. In addition, the data suggest a potential new role for genomic imprinting at the IgfII / H19 locus affecting maternal behavior.
Abstract Context Insulin-like growth factor (IGF) signaling is essential for achieving optimal body size during fetal development, peak bone mass during puberty, and maximal fecundity in the ...reproductive period. IGF-II is considered the main fetal IGF, whereas IGF-I is more important postnatally. Pregnancy-associated plasma protein-A (PAPP-A) enhances local IGF signaling through cleavage of inhibitory IGF binding proteins. Conversely, inhibition of PAPP-A results in reduced local IGF action. Thus, PAPP-A knock-out (KO) mice are born as proportional dwarfs due to the dysregulation of IGF-II signaling during early embryogenesis that impacts body size. Relaxation of IgfII imprinting through mutation of a reciprocally imprinted downstream gene, H19 , which allowed transcription of IGF-II from the normally silent maternal allele, rescued the dwarf phenotype of PAPP-A KO mice. Objective To determine the effect of increased IGF-II expression on postnatal phenotypes of PAPP-A KO mice. Design Young adult wild-type (WT), PAPP-A KO, H19 mutant (ΔH19/WT) and ΔH19/PAPP-A KO mice were characterized for skeletal phenotype (peripheral quantitative computed tomography at the midshaft and distal metaphysis of the femur) and reproductive phenotype (time to first litter, time between litters, pups per litter). Results Serum IGF-II levels were significantly increased in ΔH19/WT and ΔH19/PAPP-A KO mice compared to WT and PAPP-A KO mice; serum IGF-I levels were not affected by H19 mutation. PAPP-A KO mice had reductions in cortical thickness and in cortical and trabecular area, bone mineral content and bone mineral density compared to WT mice. There were no significant differences between PAPP-A KO and ΔH19/PAPP-A KO mice in any of the bone parameters. PAPP-A KO crossed with (×) PAPP-A KO had a longer time until first litter, normal time between subsequent litters, and significantly reduced number of pups per litter compared to WT × WT. ΔH19/PAPP-A KO × ΔH19/PAPP-A KO had an even longer time to first litter, but also longer time between litters. This phenotype was associated with female ΔH19/PAPP-A KO mice. Furthermore, these ΔH19/PAPP-A KO mouse mothers failed to care for their pups. Conclusions An increase in IGF-II expression did not rescue the skeletal and reproductive deficiencies associated with reduced local IGF-I signaling in PAPP-A KO mice. In addition, the data suggest a potential new role for genomic imprinting at the IgfII / H19 locus affecting maternal behavior.
Abstract Context Insulin-like growth factor (IGF) signaling is essential for achieving optimal body size during fetal development, peak bone mass during puberty, and maximal fecundity in the ...reproductive period. IGF-II is considered the main fetal IGF, whereas IGF-I is more important postnatally. Pregnancy-associated plasma protein-A (PAPP-A) enhances local IGF signaling through cleavage of inhibitory IGF binding proteins. Conversely, inhibition of PAPP-A results in reduced local IGF action. Thus, PAPP-A knock-out (KO) mice are born as proportional dwarfs due to the dysregulation of IGF-II signaling during early embryogenesis that impacts body size. Relaxation of IgfII imprinting through mutation of a reciprocally imprinted downstream gene, H19 , which allowed transcription of IGF-II from the normally silent maternal allele, rescued the dwarf phenotype of PAPP-A KO mice. Objective To determine the effect of increased IGF-II expression on postnatal phenotypes of PAPP-A KO mice. Design Young adult wild-type (WT), PAPP-A KO, H19 mutant (ΔH19/WT) and ΔH19/PAPP-A KO mice were characterized for skeletal phenotype (peripheral quantitative computed tomography at the midshaft and distal metaphysis of the femur) and reproductive phenotype (time to first litter, time between litters, pups per litter). Results Serum IGF-II levels were significantly increased in ΔH19/WT and ΔH19/PAPP-A KO mice compared to WT and PAPP-A KO mice; serum IGF-I levels were not affected by H19 mutation. PAPP-A KO mice had reductions in cortical thickness and in cortical and trabecular area, bone mineral content and bone mineral density compared to WT mice. There were no significant differences between PAPP-A KO and ΔH19/PAPP-A KO mice in any of the bone parameters. PAPP-A KO crossed with (×) PAPP-A KO had a longer time until first litter, normal time between subsequent litters, and significantly reduced number of pups per litter compared to WT × WT. ΔH19/PAPP-A KO × ΔH19/PAPP-A KO had an even longer time to first litter, but also longer time between litters. This phenotype was associated with female ΔH19/PAPP-A KO mice. Furthermore, these ΔH19/PAPP-A KO mouse mothers failed to care for their pups. Conclusions An increase in IGF-II expression did not rescue the skeletal and reproductive deficiencies associated with reduced local IGF-I signaling in PAPP-A KO mice. In addition, the data suggest a potential new role for genomic imprinting at the IgfII / H19 locus affecting maternal behavior.
Background and Objectives
We sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects.
Methods
Septin‐IgGs were detected by indirect ...immunofluorescence assays (IFAs; mouse tissue and cell based) or Western blot. IgG binding to (and internalization of) extracellular septin epitopes were evaluated for by live rat hippocampal neuron assay. The impact of purified patient IgGs on murine cortical neuron function was determined by recording extracellular field potentials in a multielectrode array platform.
Results
Septin‐IgGs were identified in 23 patients. All 8 patients with septin‐5‐IgG detected had cerebellar ataxia, and 7 had prominent eye movement disorders. One of 2 patients with co‐existing septin‐7‐IgG had additional psychiatric phenotype (apathy, emotional blunting, and poor insight). Fifteen patients had septin‐7 autoimmunity, without septin‐5‐IgG detected. Disorders included encephalopathy (11; 2 patients with accompanying myelopathy, and 2 were relapsing), myelopathy (3), and episodic ataxia (1). Psychiatric symptoms (≥1 of agitation, apathy, catatonia, disorganized thinking, and paranoia) were prominent in 6 of 11 patients with encephalopathic symptoms. Eight of 10 patients with data available (from 23 total) improved after immunotherapy, and a further 2 patients improved spontaneously. Staining of plasma membranes of live hippocampal neurons produced by patient IgGs (subclasses 1 and 2) colocalized with pre‐ and post‐synaptic markers. Decreased spiking and bursting behavior in mixed cultures of murine glutamatergic and GABAergic cortical neurons produced by patient IgGs were attributable to neither antigenic crosslinking and internalization nor complement activation.
Interpretation
Septin‐IgGs are predictive of distinct treatment‐responsive autoimmune central nervous system (CNS) disorders. Live neuron binding and induced electrophysiologic effects by patient IgGs may support septin‐specific pathophysiology. ANN NEUROL 2022;92:1090–1101
Tumor-selective oncolytic vesicular stomatitis viruses (VSVs) are being evaluated in clinical trials. Here, we report that the MPC-11 murine plasmacytoma model is so extraordinarily susceptible to ...oncolytic VSVs that a low dose of virus leads to extensive intratumoral viral replication, sustained viremia, intravascular coagulation, and a rapidly fatal tumor lysis syndrome (TLS). Rapid softening, shrinkage and hemorrhagic necrosis of flank tumors was noted within 1–2 days after virus administration, leading to hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, increase in plasma cell free DNA, lymphopenia, consumptive coagulopathy, increase in fibrinogen degradation products, decreased liver function tests, dehydration, weight loss, and euthanasia or death after 5–8 days. Secondary viremia was observed but viral replication in normal host tissues was not detected. Toxicity could be mitigated by using VSVs with slowed replication kinetics, and was less marked in animals with smaller flank tumors. The MPC-11 tumor represents an interesting model to further study the complex interplay of robust intratumoral viral replication, tumor lysis, and associated toxicities in cases where tumors are highly responsive to oncolytic virotherapy.
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