Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutation that exhibits a pleiotropic phenotype that includes embryonic and perinatal lethality. The embryologic defects in acd mutant embryos consist of truncation of the posterior body axis, vertebral segmentation defects, hydronephrosis, and limb anomalies, resembling common malformations observed in humans with caudal regression syndrome (CRS) and VACTERL (vertebral, anal, cardiac, tracheo-esophageal fistula, renal, limb anomalies) association. In addition, acd mutant embryos exhibit growth retardation, widespread apoptosis, vascular patterning defects, and abnormalities in hematopoietic stem cell populations. The Acd gene encodes a novel telomeric binding protein (also known as TPP1) that functions in a multiprotein complex to maintain telomere integrity. Consistent with this function, acd mutant mice have evidence of telomere dysfunction, indicative of genomic instability. While the association between genomic instability and cancer is well documented, the association between genomic instability and birth defects in humans is unexplored. VACTERL and VACTERL-like defects have been reported in other genetic syndromes characterized by genomic instability, including Fanconi anemia and Rothmund-Thomson syndrome;however, the mechanisms that lead to birth defects in these syndromes are unknown. The overall goal of this project is to understand the mechanisms that lead to birth defects resulting from genomic instability, including CRS and VACTERL, using the acd mouse as a model system. The acd mouse is an outstanding model for these studies because it exhibits cellular evidence of genomic instability and malformations that resemble CRS and VACTERL. This work is important because the underlying mechanisms leading to CRS and VACTERL in humans are likely to be similar.
In Aim 1, interactions between Acd and p53 family members, which have a well-known role in maintaining genomic stability, will be explored. These studies will build upon prior work in this laboratory showing that aspects of the acd phenotype, specifically the vertebral anomalies and limb hypoplasia, are due to p53-dependent apoptosis.
In Aim 2, the hypothesis that normal Acd function is critical during early organogenesis will be tested using an inducible targeted knockout of the Acd gene during development.
Aim 3 will investigate the role of Acd in hematopoietic stem cell survival and maintenance.
In Aim 4, domain-specific phenotypes of Acd will be examined in vivo using transgenic mouse models. The use of the acd mouse model to elucidate the mechanisms underlying common birth defects in humans, such as CRS and VACTERL, is a critical step toward identification of causative genetic and environmental factors in humans. The information gained from these studies may ultimately lead to treatment and prevention of these birth defects.

Public Health Relevance

Birth defects are the leading cause of infant mortality in the United States, accounting for 1 in 5 infant deaths annually. The adrenocortical dysplasia (acd) mouse is a model for caudal regression syndrome and VACTERL (vertebral, anal, cardiac, tracheo-esophageal fistula, renal, and limb anomalies) association in humans, and the Acd gene encodes a protein that has a role in telomere protection and genome stability. The role of genomic instability as a cause of birth defects is unexplored;therefore, the goal of this proposal is to use the acd mouse model to help understand the link between genomic instability and birth defects. The information gained from these studies will be a critical step toward identification of causative genetic and environmental factors that lead to birth defects in humans and may ultimately lead to treatment and prevention of these birth defects.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Javois, Lorette Claire
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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