Microcephalia with mandibular and dental dysplasia in adult Zmpste24‐deficient mice

Abstract

ZMPSTE24 (also called FACE-1) is a zinc-metalloprotease involved in the post-translational processing of prelamin A to mature lamin A, a major component of the nuclear envelope. Mutations in the ZMPSTE24 gene or in that encoding its substrate prelamin A ( LMNA ) result in a series of human inherited diseases known collectively as laminopathies and showing regional or systemic manifestations (i.e. the Hutchinson-Gilford progeria syndrome). Typically, patients suffering some laminopathies show craniofacial or mandible anomalies, aberrant dentition or facial features characteristic of aged persons. To analyse whether Zmpste24 -/-mice reproduce the cranial phenotype observed in humans due to mutations in ZMPSTE24 or LMNA , we conducted a craniometric study based on micro-computer tomography ( μ CT) images. Furthermore, using simple radiology, μ CT, μ CT-densitometry and scanning electron microscopy, we analysed the mandible and the teeth from Zmpste24 -/-mice. Finally, the structure of the lower incisor was investigated using an H&E technique. The results demonstrate that Zmpste24 -/-mice are microcephalic and show mandibular and dental dysplasia affecting only the mandible teeth. In all cases, the lower incisor of mice lacking Zmpste24 was smaller than in control animals, showed cylindrical morphology and a transverse fissure at the incisal edge, and the pulpal cavity was severely reduced. Structurally, the dental layers were normally arranged but cellular layers were disorganized. The inferior molars showed a reduced cusp size. Taken together, these data strongly suggest that Zmpste24 -/-mice represent a good model to analyse the craniofacial and teeth malformations characteristic of lamin-related pathologies, and might contribute to a better understanding of the molecular events underlying these diseases.

Sclerostin Antibody–Induced Changes in Bone Mass Are Site Specific in Developing Crania

“…(24) Murine cranial development has been used extensively to evaluate genetic impact on human cranial bone development, and 3D micro-CT has been assessed to validate the mouse cranium as a relevant model for clinical features of OI (25) and other genetic disorders. (26) Although Scl-Ab has been explored in many simulated disease models of low bone mass resulting from ovariectomy, (27,28) orchidectomy, (29) glucocorticoid exposure, (30) disuse, (31,32) spinal cord injury, (33) rotator cuff healing, (34) and fracture repair, (35,36) these studies and others were typically performed in mature animals where most cranial developmental processes are complete. Similarly, in studies of young OI mice, the effects of pharmacologic sclerostin inhibition on the cranium during periods of rapid growth and development have not yet been described.…”

Expression of the Hutchinson-Gilford Progeria Mutation during Osteoblast Development Results in Loss of Osteocytes, Irregular Mineralization, and Poor Biomechanical Properties

“…Homozygous lmna HG/HG mice, that express progerin exclusively and no lamin A or C, displayed severe bone abnormalities, including spontaneous bone fractures in the extremities, poorly mineralized bones and premature death (21). In addition to skeletal abnormalities, Zmpste24-deficient mice also showed malformation of the teeth (15,22).…”

Accelerated ageing: from mechanism to therapy through animal models

“…Accordingly, Face-1/Zmpste24-deficient mice accumulate farnesylated prelamin A at the nuclear envelope and phenocopy human HGPS, providing a valuable animal model for the study of this pathology (Pendas et al 2002;Bergo et al 2002;Cadinanos et al 2005;de Carlos et al 2008). Using transcriptional profiling on tissues from this knockout model, we found that hyperactivation of p53 signalling plays a key role in the accelerated ageing phenotype, which is partially reversed by p53 deficiency .…”