NDLI: Generation of Mice Lacking DUF1220 Protein Domains: Effects on Fecundity and Hyperactivity

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Generation of Mice Lacking DUF1220 Protein Domains: Effects on Fecundity and Hyperactivity

Content Provider	Springer Nature Link
Author	Keeney, J. G. O’Bleness, M. S. Anderson, N. Davis, J. M. Arevalo, N. Busquet, N. Chick, W. Rozman, J. Hölter, S. M. Garrett, L. Horsch, M. Beckers, J. Wurst, W. Klingenspor, M. Restrepo, D. Angelis, M. Hrabě Sikela, J. M.
Copyright Year	2014
Abstract	Sequences encoding DUF1220 protein domains show the most extreme human lineage-specific copy number increase of any coding region in the genome and have been linked to human brain evolution. In addition, DUF1220 copy number (dosage) has been implicated in influencing brain size within the human species, both in normal populations and in individuals associated with brain size pathologies (1q21-associated microcephaly and macrocephaly). More recently, increasing dosage of a subtype of DUF1220 has been linked with increasing severity of the primary symptoms of autism. Despite these intriguing associations, a function for these domains has not been described. As a first step in addressing this question, we have developed the first transgenic model of DUF1220 function by removing the single DUF1220 domain (the ancestral form) encoded in the mouse genome. In a hypothesis generating exercise, these mice were evaluated by 197 different phenotype measurements. While resulting DUF1220-minus (KO) mice show no obvious anatomical peculiarities, they exhibit a significantly reduced fecundity (χ 2 = 19.1, df = 2, p = 7.0 × 10−5). Further extensive phenotypic analyses suggest hyperactivity (p < 0.05) of DUF1220 mice and changes in gene expression levels of brain associated with distinct neurological functions and disease. Other changes that met statistical significance include an increase in plasma glucose concentration (as measured by area under the curve, AUC 0–30 and AUC 30–120) in male mutants, fasting glucose levels, reduce sodium levels in male mutants, increased levels of the liver functional indicator ALAT/GPT in males, levels of alkaline phosphatase (also an indicator of liver function), mean R and SR amplitude by electrocardiography, elevated IgG3 levels, a reduced ratio of CD4:CD8 cells, and a reduced frequency of T cells; though it should be noted that many of these differences are quite small and require further examination. The linking of DUF1220 loss to a hyperactive phenotype is consistent with separate findings in which DUF1220 over expression results in a down-regulation of mitochondrial function, and potentially suggests a role in developmental metabolism. Finally, the substantially reduced fecundity we observe associated with KO mice argues that the ancestral DUF1220 domain provides an important biological functionthat is critical to survivability and reproductive success.
Starting Page	33
Ending Page	42
Page Count	10
File Format	PDF
ISSN	09388990
Journal	Mammalian Genome
Volume Number	26
Issue Number	1-2
e-ISSN	14321777
Language	English
Publisher	Springer US
Publisher Date	2014-10-12
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Cell Biology Anatomy Zoology
Content Type	Text
Resource Type	Article
Subject	Genetics

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