A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size

Autosomal recessive primary microcephaly is a potential model in which to research genes involved in human brain growth. We show that two forms of the disorder result from homozygous mutations in the genes CDK5RAP2 and CENPJ. We found neuroepithelial expression of the genes during prenatal neurogenesis and protein localization to the spindle poles of mitotic cells, suggesting that a centrosomal mechanism controls neuron number in the developing mammalian brain.     

New models of collaboration in genome-wide association studies: the Genetic Association Information Network

The Genetic Association Information Network (GAIN) is a public-private partnership established to investigate the genetic basis of common diseases through a series of collaborative genome-wide association studies. GAIN has used new approaches for project selection, data deposition and distribution, collaborative analysis, publication and protection from premature intellectual property claims. These demonstrate a new commitment to shared scientific knowledge that should facilitate rapid advances in understanding the genetics of complex diseases.     

Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects

Mutations in genes encoding ribosomal proteins cause the Minute phenotype in Drosophila and mice, and Diamond-Blackfan syndrome in humans. Here we report two mouse dark skin (Dsk) loci caused by mutations in Rps19 (ribosomal protein S19) and Rps20 (ribosomal protein S20). We identify a common pathophysiologic program in which p53 stabilization stimulates Kit ligand expression, and, consequently, epidermal melanocytosis via a paracrine mechanism. Accumulation of p53 also causes reduced body size and erythrocyte count. These results provide a mechanistic explanation for the diverse collection of phenotypes that accompany reduced dosage of genes encoding ribosomal proteins, and have implications for understanding normal human variation and human disease.     

A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures

We report a recurrent microdeletion syndrome causing mental retardation, epilepsy and variable facial and digital dysmorphisms. We describe nine affected individuals, including six probands: two with de novo deletions, two who inherited the deletion from an affected parent and two with unknown inheritance. The proximal breakpoint of the largest deletion is contiguous with breakpoint 3 (BP3) of the Prader-Willi and Angelman syndrome region, extending 3.95 Mb distally to BP5. A smaller 1.5-Mb deletion has a proximal breakpoint within the larger deletion (BP4) and shares the same distal BP5. This recurrent 1.5-Mb deletion contains six genes, including a candidate gene for epilepsy (CHRNA7) that is probably responsible for the observed seizure phenotype. The BP4-BP5 region undergoes frequent inversion, suggesting a possible link between this inversion polymorphism and recurrent deletion. The frequency of these microdeletions in mental retardation cases is approximately 0.3% (6/2,082 tested), a prevalence comparable to that of Williams, Angelman and Prader-Willi syndromes.     

Relative and seasonal abundance of three bark beetle predators (Coleoptera: Trogositidae, Cleridae) across an elevation gradient in ponderosa pine forests of north central Arizona

We examined abundance and flight periodicity of 3 predators of bark beetles (Coleoptera: Curculionidae, Scolytinae), Temnochila chlorodia (Mannerheim) (Coleoptera: Trogositidae), Enoclerus sphegeus (Fabricius) (Coleoptera: Cleridae), and E. lecontei (Wolcott) (Coleoptera: Cleridae), across an elevational gradient of ponderosa pine ( Pinus ponderosa Lawson) forests in north central Arizona. Predator populations were estimated at 10 sites in each of 3 elevation bands (low: 1600–1736 m; mid: 2058–2230 m; high: 2505–2651 m) for 3 years (2004–2006) using pheromone-baited funnel traps targeting 3 primary bark beetle species. We also investigated how predator abundance and flight seasonality related to those of 5 bark beetle species: Ips pini (Say), I. lecontei Swaine, Dendroctonus frontalis Zimmermann, D. brevicomis LeConte, and D. adjunctus Blandford. Temnochila chlorodia was most abundant in the low- and mid-elevation bands, whereas E. sphegeus was most abundant in the high-elevation band. Enoclerus lecontei showed no consistent elevational trend in abundance. Within each elevation band, changes in annual abundance of pooled predator species tracked shifts in abundance of pooled bark beetle species. In general, predator flight initiation coincided with or closely followed bark beetle flight initiation in the spring, but predator flight terminated before flight activity ended for most bark beetle species in the fall. In addition, the ratio of prey to predators was lowest in the summer and highest in the fall. This suggests that all bark beetle species examined may be provided temporal escape from their predators in the fall. For all 3 predator species, the pheromone-baited trap targeting D. brevicomis was less attractive than the pheromone-baited traps targeting I. pini and I. lecontei.     

Role of p21-activated kinases in cardiovascular development and function

p21-activated kinases (Paks) are a group of six serine/threonine kinases (Pak1-6) that are involved in a variety of biological processes. Recently, Paks, more specifically Pak1, -2, and -4, have been shown to play important roles in cardiovascular development and function in a range of model organisms including zebrafish and mice. These functions include proper morphogenesis and conductance of the heart, cardiac contractility, and development and integrity of the vasculature. The mechanisms underlying these effects are not fully known, but they likely differ among the various Pak isoforms and include both kinase-dependent and -independent functions. In this review, we discuss aspects of Pak function relevant to cardiovascular biology as well as potential therapeutic implications of small-molecule Pak inhibitors in cardiovascular disease.     

Functional analysis of secreted and transmembrane proteins critical to mouse development.

We describe the successful application of a modified gene-trap approach, the secretory trap, to systematically analyze the functions in vivo of large numbers of genes encoding secreted and membrane proteins. Secretory-trap insertions in embryonic stem cells can be transmitted to the germ line of mice with high efficiency and effectively mutate the target gene. Of 60 insertions analyzed in mice, one-third cause recessive lethal phenotypes affecting various stages of embryonic and postnatal development. Thus, secretory-trap mutagenesis can be used for a genome-wide functional analysis of cell signaling pathways that are critical for normal mammalian development and physiology.