The Effect of Tsc1 Deletion on Craniofacial Bone Development

Abstract

Cranial base is important to the development of craniofacial skeleton since it is connected to face and cranial vault, functioning as a supporting platform of brain and foundation structure of skull. Developmental defects in the cranial base may lead to clinical symptoms such as midfacial hypoplasia. Synchondroses in the cranial base, including ISS (intersphenoid synchondrosis) and SOS (spheno-occipital synchondrosis), are growth centers and critical to the development of cranial facial bone. The aim of this study is to determine the effect of Tsc1 deletion in chondrocytes on the craniofacial bone development. The part I pilot study showed that the CKOP0-Cre, CKOCol2a1-Cre and CKOATC-Cre mice had disrupted skull development with varied severity and distinct changes in synchondroses. The difference in phenotypes suggested different roles of Tsc1 gene at different differentiation stages of chondrocyte. The part II study focused on the Col2a1-Cre model. Tsc1 deletion by Col2a1-Cre led to skull defects in mice including a decrease in the length of cranial base; a decrease in facial width and height; and rounder cranial cavity. Besides morphological change, both ISS and SOS were significantly expanded in the CKOCol2a1-Cre mice, primarily by increased cell number and size in the resting zone. We present a model to conclude the study that upregulated mTORC1 activity led to abnormally high expression of IHH and PTHrP-r in resting zone chondrocytes, which may lead to the premature differentiation and the failure to transition into proliferative zone, resulting in the accumulation of cells in the resting zone with consequent expansion of the resting zone.