Human linkage studies have shown that genetic mutations related to cholesterol metabolism and high maternal cholesterol diets result in craniofacial bone deformities, suggesting that cholesterol metabolic aberrations may be a widely conserved mechanism in craniofacial developmental defects. However, it is still largely unknown how altered cholesterol metabolism causes craniofacial bone abnormalities. Therefore, the objective of this application is to define how cholesterol metabolic aberrations, through disruption of either the Dhcr7 gene (which encodes an enzyme involved in the last step of cholesterol synthesis and is the causative gene for Smith-Lemli-Opitz syndrome) or the Insig1 and Insig2 genes (which provide instructions for endoplasmic reticulum proteins that regulate lipid biosynthesis), cause osteoblast (OB) differentiation abnormalities, and to test the functional significance of downstream target molecules during craniofacial bone formation. The long- term goal of this project is to gain insight into the mechanisms of craniofacial bone formation and provide new medications and diagnostic tools for bone diseases. We will test our working hypothesis by using mouse genetics and cellular biology approaches. In our preliminary studies, we found that: 1) impaired cholesterol synthesis resulted in accelerated bone formation; 2) excess cholesterol synthesis resulted in decreased bone formation; 3) the formation of primary cilia, which play a crucial in sensing cell signals, was altered in OBs from Dhcr7 knockout (KO) and neural crest specific Insig1/2 conditional knockout (cKO) mice; 4) WNT signaling was altered in Dhcr7 KO and Insig1/2 cKO mice; and 5) normalization of cholesterol metabolic aberrations restored craniofacial bone defects in Dhcr7 KO and Insig1/2 cKO mice. Our hypothesis that proper cholesterol metabolism is crucial for normal craniofacial bone formation will be tested in the following specific aims: 1) to determine the role of cholesterol metabolism in craniofacial bone development; and 2) to determine the role of cholesterol metabolism in primary cilium formation in bone. This study will unravel a new mechanism of bone development and homeostasis and will lead to innovative methods of diagnosis, treatment, and prevention of skull deformities.
Craniofacial skeletal defects are one of the most prominent genetic disorders. However, the etiology of these defects remains largely unclear. Our proposed study will provide a new insight into cholesterol metabolism in craniofacial skeletal development, and will hopefully have a significant impact on the therapeutics of various types of bone diseases.
|Suzuki, Akiko; Minamide, Ryohei; Iwata, Junichi (2018) The role of acetyltransferases for the temporal-specific accessibility of ?-catenin to the myogenic gene locus. Sci Rep 8:15057|
|Suzuki, Akiko; Abdallah, Nada; Gajera, Mona et al. (2018) Genes and microRNAs associated with mouse cleft palate: A systematic review and bioinformatics analysis. Mech Dev 150:21-27|
|Suzuki, Akiko; Jun, Goo; Abdallah, Nada et al. (2018) Gene datasets associated with mouse cleft palate. Data Brief 18:655-673|
|Carlock, C; Wu, J; Shim, J et al. (2017) Interleukin33 deficiency causes tau abnormality and neurodegeneration with Alzheimer-like symptoms in aged mice. Transl Psychiatry 7:e1164|