Human microphthalmia associated with mutations in the retinal homeobox gene CHX10.

Isolated human microphthalmia/anophthalmia, a cause of congenital blindness, is a clinically and genetically heterogeneous developmental disorder characterized by a small eye and other ocular abnormalities. Three microphthalmia/anophthalmia loci have been identified, and two others have been inferred by the co-segregation of translocations with the phenotype. We previously found that mice with ocular retardation (the or-J allele), a microphthalmia phenotype, have a null mutation in the retinal homeobox gene Chx10 (refs 7,8). We report here the mapping of a human microphthalmia locus on chromosome 14q24.3, the cloning of CHX10 at this locus and the identification of recessive CHX10 mutations in two families with non-syndromic microphthalmia (MIM 251600), cataracts and severe abnormalities of the iris. In affected individuals, a highly conserved arginine residue in the DNA-recognition helix of the homeodomain is replaced by glutamine or proline (R200Q and R200P, respectively). Identification of the CHX10 consensus DNA-binding sequence (TAATTAGC) allowed us to demonstrate that both mutations severely disrupt CHX10 function. Human CHX10 is expressed in progenitor cells of the developing neuroretina and in the inner nuclear layer of the mature retina. The strong conservation in vertebrates of the CHX10 sequence, pattern of expression and loss-of-function phenotypes demonstrates the evolutionary importance of the genetic network through which this gene regulates eye development.

Retinal stem cells in the adult mammalian eye.

The mature mammalian retina is thought to lack regenerative capacity. Here, we report the identification of a stem cell in the adult mouse eye, which represents a possible substrate for retinal regeneration. Single pigmented ciliary margin cells clonally proliferate in vitro to form sphere colonies of cells that can differentiate into retinal-specific cell types, including rod photoreceptors, bipolar neurons, and Müller glia. Adult retinal stem cells are localized to the pigmented ciliary margin and not to the central and peripheral retinal pigmented epithelium, indicating that these cells may be homologous to those found in the eye germinal zone of other nonmammalian vertebrates.

The NIH's Funding to US Dental Institutions from 2005 to 2014.

This study examines funding from the National Institutes of Health (NIH) to US dental institutions between 2005 and 2014 based on publicly available data from the NIH Research Portfolio Online Reporting Tools. Over the 10-y span, 56 US dental institutions received approximately $2.2 billion from 20 Institutes, Centers, and Offices at the NIH. The National Institute of Dental and Craniofacial Research (NIDCR) is the largest NIH supporter of dental institutions, having invested 70% of the NIH total, about $1.5 billion. The NIDCR is also the primary supporter of research training and career development, as it has invested $177 million, which represents 92% of the total NIH investment of $192 million. Over the past 10 y, about half of the NIDCR's extramural award dollars have gone to dental schools, while the NIH has invested about 1%. There has been an approximately 10% net decrease in extramural dollars awarded to dental institutions over the past decade; however, given the year-to-year variability in support to dental institutions, it is unclear if this net decline reflects a long-term trend. In addition, there was an overall reduction in the extramural dollars awarded by the NIDCR and by the NIH. For example, from 2005 to 2014, the total NIDCR budget for extramural research decreased by roughly 4%, which represents a decrease of $20 million to dental institutions. After adjusting for inflation, the decline in funding to dental institutions from the NIDCR and NIH was approximately 30%. Although the NIDCR and NIH continue to invest in dental institutions, if the current decline were to continue, it could negatively affect the research conducted at dental institutions. Therefore, we discuss opportunities for dental institutions to increase NIDCR and NIH support and improve their capacity for research, research training, and career development.

Transcription factor genes and the developing eye: a genetic perspective.

We review the current knowledge of transcription factors in mammallan eye development. The 14 transcription factors presently known to be required for eye formation are examined in some detail, incorporating data from both humans and rodents. Aspects of the biochemistry, expression patterns, genetics, mutant phenotypes, and biological insights acquired from the examination of loss-of-function mutations are summarized. The other 32 tissue-restricted transcription factors that are currently known to be expressed in the developing or mature mammallan eye are tabulated, together with the timing and site of their ocular expression; the requirement for most of these genes in the eye is unknown. Contributions to mammallan eye development from the study of the genetics of the Drosophila eye are discussed briefly. Identification of the entire cohort of transcription factors required for eye development is an essential first step towards understanding the mechanisms underlying eye morphogenesis and differentiation, and the molecular basis of inherited eye abnormalities in humans.