Loss of the putative catalytic domain of HDAC4 leads to reduced thermal nociception and seizures while allowing normal bone development.
Histone deacetylase 4 (HDAC4) has been associated with muscle & bone development [1]-[6]. N-terminal MEF2 and RUNX2 binding domains of HDAC4 have been shown to mediate these effects in vitro. A complete gene knockout has been reported to result in premature ossification and associated defects resulting in postnatal lethality [6]. We report a viral insertion mutation that deletes the putative deacetylase domain, while preserving the N-terminal portion of the protein. Western blot and immuno-precipitation analysis confirm expression of truncated HDAC4 containing N-terminal amino acids 1-747. These mutant mice are viable, living to at least one year of age with no gross defects in muscle or bone. At 2-4 months of age no behavioral or physiological abnormalities were detected except for an increased latency to respond to a thermal nociceptive stimulus. As the mutant mice aged past 5 months, convulsions appeared, often elicited by handling. Our findings confirm the sufficiency of the N-terminal domain for muscle and bone development, while revealing other roles of HDAC4.
Rajan
Indrani
I
Neuroscience Research, Lexicon Pharmaceuticals Inc, The Woodlands, TX, USA.
Savelieva
Katerina V
KV
Ye
Gui-Lan
GL
Wang
Ching-Yun
CY
Malbari
Murtaza M
MM
Friddle
Carl
C
Lanthorn
Thomas H
TH
Zhang
Wandong
W
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001846:Bone Development; D020134:Catalytic Domain; D017931:DNA Primers; D005260:Female; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006358:Hot Temperature; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009043:Motor Activity; D010146:Pain / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000201:enzymology*
D017931:DNA Primers; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases