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The Journal of Neuroscience, January 1, 2003, 23(1):213-222
SRC-1 Null Mice Exhibit Moderate Motor Dysfunction and Delayed
Development of Cerebellar Purkinje Cells
Eijun
Nishihara,
Hiromi
Yoshida-Komiya,
Chi-Shing
Chan,
Lan
Liao,
Ronald L.
Davis,
Bert W.
O'Malley, and
Jianming
Xu
Department of Molecular and Cellular Biology, Baylor College of
Medicine, Houston, Texas 77030
Hormones and nuclear receptors (NRs) play important roles in brain
development and function. The recently identified steroid receptor
coactivator (SRC) family contains three homologous members that can
enhance transcriptional activities of NRs and certain non-NR
transcription factors. To study the role of SRC-1 in brain development
and function, we examined the spatial and temporal expression patterns
of SRC-1 and characterized the phenotypes of brain development and
function in SRC-1 knock-out
(SRC-1 /)
mice. In the adult mouse brain, SRC-1 is highly expressed in the
olfactory bulb, hippocampus, piriform cortex, amygdala, hypothalamus, cerebellum, and brainstem. Multiple behavioral tests revealed that
SRC-1/
mice exhibit normal hippocampal function but moderate motor
dysfunction. The behavior phenotypes correlate with the spatial
distribution of the SRC family members. In most brain structures where
SRC-1 is expressed, SRC-2 is expressed at lower levels; however, SRC-3 mRNA is detectable only in the hippocampus. In the adult cerebellum, Purkinje cells (PCs) preferentially express SRC-1 over SRC-2, but SRC-2
mRNA is slightly elevated in the
SRC-1/
PCs. During embryonic development, SRC-1 is expressed in the cerebellar
primordium. SRC-2 is expressed in PCs after postnatal day (P) 10. Time
course analysis revealed that the precursors of
SRC-1/ PCs
were generated ~2 d later than wild-type precursor cells. A further
delay in
SRC-1/ PC
maturation was detected at the neonatal stage. The morphology and
number of
SRC-1/ PCs
were equivalent to wild type by P10; this timing correlated with the
early expression of SRC-2 in the
SRC-1/
PCs. These results demonstrate that the relative levels of SRC expression are region specific, and the degree of overlapping expression may influence their functional redundancy. Disruption of
SRC-1 specifically delays the PC development and maturation in early
stages and results in moderate motor dysfunction in adulthood.
Key words:
coactivator; nuclear receptor; gene expression; animal model; motor function; Purkinje cell
Copyright © 2003 Society for Neuroscience 0270-6474/03/231213-10$05.00/0
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