Targeted disruption in mice of a neural stem cell-maintaining, KRAB-Zn finger-encoding gene that has rapidly evolved in the human lineage.
Understanding the genetic basis of the physical and behavioral traits that separate humans from other primates is a challenging but intriguing topic. The adaptive functions of the expansion and/or reduction in human brain size have long been explored. From a brain transcriptome project we have identified a KRAB-Zn finger protein-encoding gene (M003-A06) that has rapidly evolved since the human-chimpanzee separation. Quantitative RT-PCR analysis of different human tissues indicates that M003-A06 expression is enriched in the human fetal brain in addition to the fetal heart. Furthermore, analysis with use of immunofluorescence staining, neurosphere culturing and Western blotting indicates that the mouse ortholog of M003-A06, Zfp568, is expressed mainly in the embryonic stem (ES) cells and fetal as well as adult neural stem cells (NSCs). Conditional gene knockout experiments in mice demonstrates that Zfp568 is both an NSC maintaining- and a brain size-regulating gene. Significantly, molecular genetic analyses show that human M003-A06 consists of 2 equilibrated allelic types, H and C, one of which (H) is human-specific. Combined contemporary genotyping and database mining have revealed interesting genetic associations between the different genotypes of M003-A06 and the human head sizes. We propose that M003-A06 is likely one of the genes contributing to the uniqueness of the human brain in comparison to other higher primates.
Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan, Republic of China.
Huan-Chieh
HC
Chien
Hurng-Yi
HY
Wang
Yi-Ning
YN
Su
Kuan-Yu
KY
Lai
Li-Chen
LC
Lu
Pau-Chung
PC
Chen
Shih-Feng
SF
Tsai
Chung-I
CI
Wu
Wu-Shiun
WS
Hsieh
Che-Kun James
CK
Shen
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D019143:Evolution, Molecular; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D055786:Gene Knockout Techniques; D005838:Genotype; D006257:Head / Q000033:anatomy & histology*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins; D009929:Organ Size; D060888:Real-Time Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism
D002352:Carrier Proteins; D009687:Nuclear Proteins; C578367:ZNF568 protein, human; C533182:Zfp568 protein, mouse