Mitral valve prolapse (MVP) affects 1 in 40 people and is the most common indication for mitral valve surgery. MVP can cause arrhythmias, heart failure, and sudden cardiac death, and to date, the causes of this disease are poorly understood. We now demonstrate that defects in primary cilia genes and their regulated pathways can cause MVP in familial and sporadic nonsyndromic MVP cases. Our expression studies and genetic ablation experiments confirmed a role for primary cilia in regulating ECM deposition during cardiac development. Loss of primary cilia during development resulted in progressive myxomatous degeneration and profound mitral valve pathology in the adult setting. Analysis of a large family with inherited, autosomal dominant nonsyndromic MVP identified a deleterious missense mutation in a cilia gene, DZIP1. A mouse model harboring this variant confirmed the pathogenicity of this mutation and revealed impaired ciliogenesis during development, which progressed to adult myxomatous valve disease and functional MVP. Relevance of primary cilia in common forms of MVP was tested using pathway enrichment in a large population of patients with MVP and controls from previously generated genome-wide association studies (GWAS), which confirmed the involvement of primary cilia genes in MVP. Together, our studies establish a developmental basis for MVP through altered cilia-dependent regulation of ECM and suggest that defects in primary cilia genes can be causative to disease phenotype in some patients with MVP.

A common feature of Drosophila homoeo box genes appears to be their spatially restricted expression patterns during morphogenesis. Using Northern blot analysis and in situ hybridization to mouse tissue sections, the spatially restricted expression of a newly identified mouse homoeo box locus, Hox-3, within the central nervous system of newborn and adult mice has been demonstrated.

It is increasingly evident that the molecular mechanisms underlying hair follicle differentiation and cycling recapitulate principles of embryonic patterning and organ regeneration. Here we used Hoxc13-overexpressing transgenic mice (also known as GC13 mice), known to develop severe hair growth defects and alopecia, as a tool for defining pathways of hair follicle differentiation. Gene array analysis performed with RNA from postnatal skin revealed differential expression of distinct subsets of genes specific for cells of the three major hair shaft compartments (cuticle, cortex, and medulla) and their precursors. This finding correlates well with the structural defects observed in each of these compartments and implicates Hoxc13 in diverse pathways of hair follicle differentiation. The group of medulla-specific genes was particularly intriguing because this included the developmentally regulated transcription factor-encoding gene Foxq1 that is altered in the medulladefective satin mouse hair mutant. We provide evidence that Foxq1 is a downstream target for Hoxc13 based on DNA binding studies as well as co-transfection and chromatin immunoprecipitation assays. Expression of additional medulla-specific genes down-regulated upon overexpression of Hoxc13 requires functional Foxq1 as their expression is ablated in hair follicles of satin mice. Combined, these results demonstrate that Hoxc13 and Foxq1 control medulla differentiation through a common regulatory pathway. The apparent regulatory interactions between members of the mammalian Hox and Fox gene families shown here may establish a paradigm for "cross-talk" between these two conserved regulatory gene families in different developmental contexts including embryonic patterning as well as organ development and renewal.

The evolutionarily conserved Hox gene family of transcriptional regulators has originally been known for specifying positional identities along the longitudinal body axis of bilateral metazoans, including mouse and man. It is believed that subsequent to this archaic role, subsets of Hox genes have been co-opted for patterning functions in phylogenetically more recent structures, such as limbs and epithelial appendages. Among these, the hair follicle is of particular interest, as it is the only organ undergoing cyclical phases of regression and regeneration during the entire life span of an organism. Furthermore, the hair follicle is increasingly capturing the attention of developmental geneticists, as this abundantly available miniature organ mimics key aspects of embryonic patterning and, in addition, presents a model for studying organ renewal. The first Hox gene shown to play a universal role in hair follicle development is Hoxc13, as both Hoxc13-deficient and overexpressing mice exhibit severe hair growth and patterning defects. Differential gene expression analyses in the skin of these mutants, as well as in vitro DNA binding studies performed with potential targets for HOXC13 transcriptional regulation in human hair, identified genes encoding hair-specific keratins and keratin-associated proteins (KAPs) as major groups of presumptive Hoxc13 downstream effectors in the control of hair growth. The Hoxc13 mutant might thus serve as a paradigm for studying hair-specific roles of Hoxc13 and other members of this gene family, whose distinct spatio-temporally restricted expression patterns during hair development and cycling suggest discrete functions in follicular patterning and hair cycle control. The main conclusion from a discussion of these potential roles vis-à-vis current expression data in mouse and man, and from the perspective of the results obtained with the Hoxc13 transgenic models, is that members of the Hox family are likely to fulfill essential roles of great functional diversity in hair that require complex transcriptional control mechanisms to ensure proper spatio-temporal patterns of Hox gene expression at homeostatic levels.