Limits...
Nmf9 Encodes a Highly Conserved Protein Important to Neurological Function in Mice and Flies.

Zhang S, Ross KD, Seidner GA, Gorman MR, Poon TH, Wang X, Keithley EM, Lee PN, Martindale MQ, Joiner WJ, Hamilton BA - PLoS Genet. (2015)

Bottom Line: Homologous genes from unicellular organisms and invertebrate animals predict interactions with small GTPases, but the corresponding domains are absent in mammalian Nmf9.Intriguingly, homozygotes for mutations in the Drosophila homolog, CG45058, show profound locomotor defects and premature death, while heterozygotes show striking effects on sleep and activity phenotypes.These results link a novel gene orthology group to discrete neurological functions, and show conserved requirement across wide phylogenetic distance and domain level structural changes.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, La Jolla, California, United States of America.

ABSTRACT
Many protein-coding genes identified by genome sequencing remain without functional annotation or biological context. Here we define a novel protein-coding gene, Nmf9, based on a forward genetic screen for neurological function. ENU-induced and genome-edited mutations in mice produce deficits in vestibular function, fear learning and circadian behavior, which correlated with Nmf9 expression in inner ear, amygdala, and suprachiasmatic nuclei. Homologous genes from unicellular organisms and invertebrate animals predict interactions with small GTPases, but the corresponding domains are absent in mammalian Nmf9. Intriguingly, homozygotes for mutations in the Drosophila homolog, CG45058, show profound locomotor defects and premature death, while heterozygotes show striking effects on sleep and activity phenotypes. These results link a novel gene orthology group to discrete neurological functions, and show conserved requirement across wide phylogenetic distance and domain level structural changes.

No MeSH data available.


Related in: MedlinePlus

Tests of LS, PC/olfactory pathway, and VMH.Behaviors that depend on Nmf9-expressing circuits were assayed and assessed by 2-factor ANOVA or MANOVA for sex and genotype. Number tested for each group (N) is indicated in each bar or a legend to line graphs. (A) Elevated Plus Maze behaviors were not significantly different between control (+/+) and mutant (n/n) littermates (Percent time in open arm p = 0.27 for genotype, p = 0.22 for sex; Number of transitions p = 0.12 for genotype, p = 0.23 for sex). (B) In the Open Field Test, mutant animals showed increased time spent in center, but potentially confounded by increased number of line crosses due to hyperactivity (Time in center p = 0.0043 for genotype, p = 0.82 for sex; number of transitions, 3.4x10-7 for genotype, p = 0.0004 for sex). (C) No significant difference between genotypes was detected for the Marble Burying Test (p = 0.15 and 0.68 for genotype and sex, respectively). (D) While mutant females took somewhat longer in olfactory-dependent Buried Food Finding Test, this was did not reach conventional significance (p = 0.11 for genotype, 0.09 for sex). (E) Similarly, Odor Habituation / Dishabituation Tests did not support a significant difference (MANOVA, p = 0.69 for genotype, p = 0.30 for sex). (F) Weight was significantly different by genotype at 2 months (ANOVA, p = 0.014) and remained significant at 6 months (p = 0.0088), including well-known sex differences, while food consumption (G) was not significantly different (p = 0.11 for genotype, 0.75 for sex).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4488434&req=5

pgen.1005344.g005: Tests of LS, PC/olfactory pathway, and VMH.Behaviors that depend on Nmf9-expressing circuits were assayed and assessed by 2-factor ANOVA or MANOVA for sex and genotype. Number tested for each group (N) is indicated in each bar or a legend to line graphs. (A) Elevated Plus Maze behaviors were not significantly different between control (+/+) and mutant (n/n) littermates (Percent time in open arm p = 0.27 for genotype, p = 0.22 for sex; Number of transitions p = 0.12 for genotype, p = 0.23 for sex). (B) In the Open Field Test, mutant animals showed increased time spent in center, but potentially confounded by increased number of line crosses due to hyperactivity (Time in center p = 0.0043 for genotype, p = 0.82 for sex; number of transitions, 3.4x10-7 for genotype, p = 0.0004 for sex). (C) No significant difference between genotypes was detected for the Marble Burying Test (p = 0.15 and 0.68 for genotype and sex, respectively). (D) While mutant females took somewhat longer in olfactory-dependent Buried Food Finding Test, this was did not reach conventional significance (p = 0.11 for genotype, 0.09 for sex). (E) Similarly, Odor Habituation / Dishabituation Tests did not support a significant difference (MANOVA, p = 0.69 for genotype, p = 0.30 for sex). (F) Weight was significantly different by genotype at 2 months (ANOVA, p = 0.014) and remained significant at 6 months (p = 0.0088), including well-known sex differences, while food consumption (G) was not significantly different (p = 0.11 for genotype, 0.75 for sex).

Mentions: Measures of innate anxiety, which are dependent on the lateral septum, appeared intact in nmf9 mutants. Behavior on an elevated plus maze detected no significant difference between genotypes (Fig 5A). In an open field test, nmf9 mutants spent more time in the center of the open field, which could indicate a functional change in LS, but the number of line crossings was also significantly higher, suggesting that the hyperactivity and circling behaviors in nmf9 confound a simple interpretation of the open field results (Fig 5B). Marble burying, a third test of anxiety-related behavior that is less affected by activity, showed no significant difference between genotypes (Fig 5C).


Nmf9 Encodes a Highly Conserved Protein Important to Neurological Function in Mice and Flies.

Zhang S, Ross KD, Seidner GA, Gorman MR, Poon TH, Wang X, Keithley EM, Lee PN, Martindale MQ, Joiner WJ, Hamilton BA - PLoS Genet. (2015)

Tests of LS, PC/olfactory pathway, and VMH.Behaviors that depend on Nmf9-expressing circuits were assayed and assessed by 2-factor ANOVA or MANOVA for sex and genotype. Number tested for each group (N) is indicated in each bar or a legend to line graphs. (A) Elevated Plus Maze behaviors were not significantly different between control (+/+) and mutant (n/n) littermates (Percent time in open arm p = 0.27 for genotype, p = 0.22 for sex; Number of transitions p = 0.12 for genotype, p = 0.23 for sex). (B) In the Open Field Test, mutant animals showed increased time spent in center, but potentially confounded by increased number of line crosses due to hyperactivity (Time in center p = 0.0043 for genotype, p = 0.82 for sex; number of transitions, 3.4x10-7 for genotype, p = 0.0004 for sex). (C) No significant difference between genotypes was detected for the Marble Burying Test (p = 0.15 and 0.68 for genotype and sex, respectively). (D) While mutant females took somewhat longer in olfactory-dependent Buried Food Finding Test, this was did not reach conventional significance (p = 0.11 for genotype, 0.09 for sex). (E) Similarly, Odor Habituation / Dishabituation Tests did not support a significant difference (MANOVA, p = 0.69 for genotype, p = 0.30 for sex). (F) Weight was significantly different by genotype at 2 months (ANOVA, p = 0.014) and remained significant at 6 months (p = 0.0088), including well-known sex differences, while food consumption (G) was not significantly different (p = 0.11 for genotype, 0.75 for sex).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488434&req=5

pgen.1005344.g005: Tests of LS, PC/olfactory pathway, and VMH.Behaviors that depend on Nmf9-expressing circuits were assayed and assessed by 2-factor ANOVA or MANOVA for sex and genotype. Number tested for each group (N) is indicated in each bar or a legend to line graphs. (A) Elevated Plus Maze behaviors were not significantly different between control (+/+) and mutant (n/n) littermates (Percent time in open arm p = 0.27 for genotype, p = 0.22 for sex; Number of transitions p = 0.12 for genotype, p = 0.23 for sex). (B) In the Open Field Test, mutant animals showed increased time spent in center, but potentially confounded by increased number of line crosses due to hyperactivity (Time in center p = 0.0043 for genotype, p = 0.82 for sex; number of transitions, 3.4x10-7 for genotype, p = 0.0004 for sex). (C) No significant difference between genotypes was detected for the Marble Burying Test (p = 0.15 and 0.68 for genotype and sex, respectively). (D) While mutant females took somewhat longer in olfactory-dependent Buried Food Finding Test, this was did not reach conventional significance (p = 0.11 for genotype, 0.09 for sex). (E) Similarly, Odor Habituation / Dishabituation Tests did not support a significant difference (MANOVA, p = 0.69 for genotype, p = 0.30 for sex). (F) Weight was significantly different by genotype at 2 months (ANOVA, p = 0.014) and remained significant at 6 months (p = 0.0088), including well-known sex differences, while food consumption (G) was not significantly different (p = 0.11 for genotype, 0.75 for sex).
Mentions: Measures of innate anxiety, which are dependent on the lateral septum, appeared intact in nmf9 mutants. Behavior on an elevated plus maze detected no significant difference between genotypes (Fig 5A). In an open field test, nmf9 mutants spent more time in the center of the open field, which could indicate a functional change in LS, but the number of line crossings was also significantly higher, suggesting that the hyperactivity and circling behaviors in nmf9 confound a simple interpretation of the open field results (Fig 5B). Marble burying, a third test of anxiety-related behavior that is less affected by activity, showed no significant difference between genotypes (Fig 5C).

Bottom Line: Homologous genes from unicellular organisms and invertebrate animals predict interactions with small GTPases, but the corresponding domains are absent in mammalian Nmf9.Intriguingly, homozygotes for mutations in the Drosophila homolog, CG45058, show profound locomotor defects and premature death, while heterozygotes show striking effects on sleep and activity phenotypes.These results link a novel gene orthology group to discrete neurological functions, and show conserved requirement across wide phylogenetic distance and domain level structural changes.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, La Jolla, California, United States of America.

ABSTRACT
Many protein-coding genes identified by genome sequencing remain without functional annotation or biological context. Here we define a novel protein-coding gene, Nmf9, based on a forward genetic screen for neurological function. ENU-induced and genome-edited mutations in mice produce deficits in vestibular function, fear learning and circadian behavior, which correlated with Nmf9 expression in inner ear, amygdala, and suprachiasmatic nuclei. Homologous genes from unicellular organisms and invertebrate animals predict interactions with small GTPases, but the corresponding domains are absent in mammalian Nmf9. Intriguingly, homozygotes for mutations in the Drosophila homolog, CG45058, show profound locomotor defects and premature death, while heterozygotes show striking effects on sleep and activity phenotypes. These results link a novel gene orthology group to discrete neurological functions, and show conserved requirement across wide phylogenetic distance and domain level structural changes.

No MeSH data available.


Related in: MedlinePlus