Mice lacking Alkbh1 display sex-ratio distortion and unilateral eye defects.
BACKGROUND
Escherichia coli AlkB is a 2-oxoglutarate- and iron-dependent dioxygenase that reverses alkylated DNA damage by oxidative demethylation. Mouse AlkB homolog 1 (Alkbh1) is one of eight members of the newly discovered family of mammalian dioxygenases.


RESULTS
In the present study we show non-Mendelian inheritance of the Alkbh1 targeted allele in mice. Both Alkbh1(-/-) and heterozygous Alkbh1(+/-) offspring are born at a greatly reduced frequency. Additionally, the sex-ratio is considerably skewed against female offspring, with one female born for every three to four males. Most mechanisms that cause segregation distortion, act in the male gametes and affect male fertility. The skewing of the sexes appears to be of paternal origin, and might be set in the pachythene stage of meiosis during spermatogenesis, in which Alkbh1 is upregulated more than 10-fold. In testes, apoptotic spermatids were revealed in 5-10% of the tubules in Alkbh1(-/-) adults. The deficiency of Alkbh1 also causes misexpression of Bmp2, 4 and 7 at E11.5 during embryonic development. This is consistent with the incompletely penetrant phenotypes observed, particularly recurrent unilateral eye defects and craniofacial malformations.


CONCLUSIONS
Genetic and phenotypic assessment suggests that Alkbh1 mediates gene regulation in spermatogenesis, and that Alkbh1 is essential for normal sex-ratio distribution and embryonic development in mice.
Centre for Molecular Biology and Neuroscience, Institute of Medical Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.
Line M
LM
Nordstrand
Jessica
J
Svärd
Elisabeth
E
Larsen
Anja
A
Nilsen
Rune
R
Ougland
Kari
K
Furu
Guro F
GF
Lien
Torbjørn
T
Rognes
Satoshi H
SH
Namekawa
Jeannie T
JT
Lee
Arne
A
Klungland
D000071498:AlkB Homolog 1, Histone H2a Dioxygenase; D000818:Animals; D000831:Animals, Newborn; D000853:Anophthalmos / Q000235:genetics; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D049308:Dioxygenases / Q000172:deficiency / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000378:metabolism*; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008850:Microphthalmos / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012744:Sex Ratio; D013091:Spermatogenesis / Q000235:genetics; D013737:Testis / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*
C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D014157:Transcription Factors; C525820:bmp7 protein, mouse; D049308:Dioxygenases; D000071498:AlkB Homolog 1, Histone H2a Dioxygenase; C529511:Alkbh1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase