TY - JOUR
T1 - Developmental expression pattern of the cholesterogenic enzyme NSDHL and negative selection of NSDHL-deficient cells in the heterozygous Bpa1H/+ mouse
AU - Cunningham, David
AU - Spychala, Kaitlyn
AU - McLarren, Keith W.
AU - Garza, Luis A.
AU - Boerkoel, Cornelius F.
AU - Herman, Gail E.
N1 - Funding Information:
We thank Dr. Kim McBride for performing statistical analysis. This work was supported by NIH R01 HD38572 to G.E.H.
PY - 2009/12
Y1 - 2009/12
N2 - NSDHL (NAD(P)H sterol dehydrogenase-like), is a 3β-hydroxysterol dehydrogenase thought to function in the demethylation of sterol precursors in one of the later steps of cholesterol biosynthesis. Mutations in the X-linked NSDHL gene cause CHILD syndrome in humans, and the male-lethal bare patches (Bpa) phenotype in mice. The relative level of NSDHL expression among different mouse tissues at several stages of embryogenesis and postnatal development was analyzed by immunohistochemistry. In wild type (WT) embryos, the highest levels of expression were seen in the liver, dorsal root ganglia, central nervous system, retina, adrenal gland and testis. Heterozygous Bpa1H females are mosaic for NSDHL expression due to normal random X-inactivation. NSDHL-deficient cells were detected in the developing cerebral cortex and retina of Bpa1H female embryos. In postnatal WT and Bpa1H animals, we compared the expression pattern of NSDHL in skin, an affected tissue; liver, a main site of cholesterol synthesis; and brain, a tissue dependent on endogenous synthesis of cholesterol due to lack of transport across the blood-brain barrier. Clonal populations of mutant cells were visible in the brain, skin and liver of Bpa1H pups. In the liver, the proportion of NSDHL negative cells dropped from ∼50% at postnatal day 6 to ∼20% at one year of age. In the brain, which showed the highest expression in cerebral cortical and hippocampal neurons, the proportion of NSDHL negative cells also dropped dramatically over the first year of life. Our results suggest that while NSDHL-deficient cells in the mosaic Bpa1H female are able to survive and differentiate during embryonic development, they are subject to negative selection over the life of the animal.
AB - NSDHL (NAD(P)H sterol dehydrogenase-like), is a 3β-hydroxysterol dehydrogenase thought to function in the demethylation of sterol precursors in one of the later steps of cholesterol biosynthesis. Mutations in the X-linked NSDHL gene cause CHILD syndrome in humans, and the male-lethal bare patches (Bpa) phenotype in mice. The relative level of NSDHL expression among different mouse tissues at several stages of embryogenesis and postnatal development was analyzed by immunohistochemistry. In wild type (WT) embryos, the highest levels of expression were seen in the liver, dorsal root ganglia, central nervous system, retina, adrenal gland and testis. Heterozygous Bpa1H females are mosaic for NSDHL expression due to normal random X-inactivation. NSDHL-deficient cells were detected in the developing cerebral cortex and retina of Bpa1H female embryos. In postnatal WT and Bpa1H animals, we compared the expression pattern of NSDHL in skin, an affected tissue; liver, a main site of cholesterol synthesis; and brain, a tissue dependent on endogenous synthesis of cholesterol due to lack of transport across the blood-brain barrier. Clonal populations of mutant cells were visible in the brain, skin and liver of Bpa1H pups. In the liver, the proportion of NSDHL negative cells dropped from ∼50% at postnatal day 6 to ∼20% at one year of age. In the brain, which showed the highest expression in cerebral cortical and hippocampal neurons, the proportion of NSDHL negative cells also dropped dramatically over the first year of life. Our results suggest that while NSDHL-deficient cells in the mosaic Bpa1H female are able to survive and differentiate during embryonic development, they are subject to negative selection over the life of the animal.
KW - Brain
KW - CHILD syndrome
KW - Cholesterol
KW - Liver
KW - NSDHL
KW - Skin
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U2 - 10.1016/j.ymgme.2009.06.016
DO - 10.1016/j.ymgme.2009.06.016
M3 - Article
C2 - 19631568
AN - SCOPUS:70350618065
SN - 1096-7192
VL - 98
SP - 356
EP - 366
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 4
ER -