Dorsal dermis and epaxial muscle have been shown to arise from the central dermomyotome in the chick. En1 is a homeobox transcription factor gene expressed in the central dermomyotome. We show by genetic fate mapping in the mouse that En1-expressing cells of the central dermomyotome give rise to dorsal dermis and epaxial muscle and, unexpectedly, to interscapular brown fat. Thus, the En1-expressing central dermomyotome normally gives rise to three distinct fates in mice. Wnt signals are important in early stages of dermomyotome development, but the signal that acts to specify the dermal fate has not been identified. Using a reporter transgene for Wnt signal transduction, we show that the En1-expressing cells directly underneath the surface ectoderm transduce Wnt signals. When the essential Wnt transducer beta-catenin is mutated in En1 cells, it results in the loss of Dermo1-expressing dorsal dermal progenitors and dermis. Conversely, when beta-catenin was activated in En1 cells, it induces Dermo1 expression in all cells of the En1 domain and disrupts muscle gene expression. Our results indicate that the mouse central dermomyotome gives rise to dermis, muscle, and brown fat, and that Wnt signalling normally instructs cells to select the dorsal dermal fate.

Genes associated with human microcephaly, a condition characterized by a small brain, include critical regulators of proliferation, cell fate, and DNA repair. We describe a syndrome of congenital microcephaly and diverse defects in cerebral cortical architecture. Genome-wide linkage analysis in two families identified a 7.5 Mb locus on chromosome 19q13.12 containing 148 genes. Targeted high throughput sequence analysis of linked genes in each family yielded > 4000 DNA variants and implicated a single gene, WDR62, as harboring potentially deleterious changes. We subsequently identified additional WDR62 mutations in four other families. MRI and postmortem brain analysis supports important roles for WDR62 in proliferation and migration of neuronal precursors. WDR62 is a WD40 repeat-containing protein expressed in neuronal precursors as well as postmitotic neurons in the developing brain and localizes to the spindle poles of dividing cells. The diverse phenotypes of WDR62 suggest central roles in many aspects of cerebral cortical development.

BackgroundIt is commonly assumed that sexual risk factors for heterosexual HIV transmission in sub-Saharan Africa, such as multi-partner sex, paid sex and co-infections, become less important as HIV epidemics mature and prevalence increases.Methods and FindingsWe conducted a systematic review of 68 African epidemiological studies from 1986 to 2006 involving 17,000 HIV positive adults and 73,000 controls. We used random-effects methods and stratified results by gender, time, background HIV prevalence rates and other variables. The number of sex partners, history of paid sex, and infection with herpes simplex virus (HSV-2) or other sexually-transmitted infections (STIs) each showed significant associations with HIV infection. Among the general population, the odds ratio (OR) of HIV infection for women reporting 3+ sex partners versus 0–2 was 3.64 (95%CI [2.87–4.62]), with similar risks for men. About 9% of infected women reported ever having been paid for sex, versus 4% of control women (OR = 2.29, [1.45–3.62]). About 31% of infected men reported ever paying for sex versus 18% of uninfected men (OR = 1.75, [1.30–2.36]). HSV-2 infection carried the largest risk of HIV infection: OR = 4.62, [2.85–7.47] in women, and OR = 6.97, [4.68–10.38] in men. These risks changed little over time and stratification by lower and higher HIV background prevalence showed that risk ratios for most variables were larger in high prevalence settings. Among uninfected controls, the male-female differences in the number of sex partners and in paid sex were more extreme in the higher HIV prevalence settings than in the lower prevalence settings.SignificanceMulti-partner sex, paid sex, STIs and HSV-2 infection are as important to HIV transmission in advanced as in early HIV epidemics. Even in high prevalence settings, prevention among people with high rates of partner change, such as female sex workers and their male clients, is likely to reduce transmission overall.

The genetic pathways that partition the developing nervous system into functional systems are largely unknown. The engrailed (En) homeobox transcription factors are candidate regulators of this process in the dorsal midbrain (tectum) and anterior hindbrain (cerebellum). En1 mutants lack most of the tectum and cerebellum and die at birth, whereas En2 mutants are viable with a smaller cerebellum and foliation defects. Our previous studies indicated that the difference in phenotypes is due to the earlier expression of En1 as compared with En2, rather than differences in protein function, since knock-in mice expressing En2 in place of En1 have a normal brain. Here, we uncovered a wider spectrum of functions for the En genes by generating a series of En mutant mice. First, using a conditional allele we demonstrate that En1 is required for cerebellum development only before embryonic day 9, but plays a sustained role in forming the tectum. Second, by removing the endogenous En2 gene in the background of En1 knock-in alleles, we show that Drosophila en is not sufficient to sustain midbrain and cerebellum development in the absence of En2, whereas En2 is more potent than En1 in cerebellum development. Third, based on a differential sensitivity to the dose of En1/2, our studies reveal a genetic subdivision of the tectum into its two functional systems and the medial cerebellum into four regions that have distinct circuitry and molecular coding. Our study suggests that an 'engrailed code' is integral to partitioning the tectum and cerebellum into functional domains.

In this Collection Review, Sema Sgaier and colleagues highlight the key points from the PLOS Volunteer Medical Male Circumcision Collection and give some recommendations on the way forward. Please see later in the article for the Editors' Summary

SUMMARYLittle is known about the genetic pathways and cellular processes responsible for regional differences in cerebellum foliation, which interestingly are accompanied by regionally distinct afferent circuitry. We have identified the Engrailed (En) homeobox genes as being crucial to producing the distinct medial vermis and lateral hemisphere foliation patterns in mammalian cerebella. By producing a series of temporal conditional mutants in En1 and/or En2, we demonstrate that both En genes are required to ensure that folia exclusive to the vermis or hemispheres form in the appropriate mediolateral position. Furthermore, En1/En2 continue to regulate foliation after embryonic day 14, at which time Fgf8 isthmic organizer activity is complete and the major output cells of the cerebellar cortex have been specified. Changes in spatially restricted gene expression occur prior to foliation in mutants, and foliation is altered from the onset and is accompanied by changes in the thickness of the layer of proliferating granule cell precursors. In addition, the positioning and timing of fissure formation are altered. Thus, the En genes represent a new class of genes that are fundamental to patterning cerebellum foliation throughout the mediolateral axis and that act late in development.

BackgroundDespite considerable efforts to scale up voluntary medical male circumcision (VMMC) for HIV prevention in priority countries over the last five years, implementation has faced important challenges. Seeking to enhance the effect of VMMC programs for greatest and most immediate impact, the U. S. President’s Plan for AIDS Relief (PEPFAR) supported the development and application of a model to inform national planning in five countries from 2013–2014.Methods and FindingsThe Decision Makers’ Program Planning Toolkit (DMPPT) 2.0 is a simple compartmental model designed to analyze the effects of client age and geography on program impact and cost. The DMPPT 2.0 model was applied in Malawi, South Africa, Swaziland, Tanzania, and Uganda to assess the impact and cost of scaling up age-targeted VMMC coverage. The lowest number of VMMCs per HIV infection averted would be produced by circumcising males ages 20–34 in Malawi, South Africa, Tanzania, and Uganda and males ages 15–34 in Swaziland. The most immediate impact on HIV incidence would be generated by circumcising males ages 20–34 in Malawi, South Africa, Tanzania, and Uganda and males ages 20–29 in Swaziland. The greatest reductions in HIV incidence over a 15-year period would be achieved by strategies focused on males ages 10–19 in Uganda, 15–24 in Malawi and South Africa, 10–24 in Tanzania, and 15–29 in Swaziland. In all countries, the lowest cost per HIV infection averted would be achieved by circumcising males ages 15–34, although in Uganda this cost is the same as that attained by circumcising 15- to 49-year-olds.ConclusionsThe efficiency, immediacy of impact, magnitude of impact, and cost-effectiveness of VMMC scale-up are not uniform; there is important variation by age group of the males circumcised and countries should plan accordingly.

BackgroundCountries in sub-Saharan Africa are scaling-up voluntary male medical circumcision (VMMC) as an HIV intervention. Emerging challenges in these programs call for increased focus on program efficiency (optimizing program impact while minimizing cost). A novel analytic approach was developed to determine how subpopulation prioritization can increase program efficiency using an illustrative application for Zambia.Methods and FindingsA population-level mathematical model was constructed describing the heterosexual HIV epidemic and impact of VMMC programs (age-structured mathematical (ASM) model). The model stratified the population according to sex, circumcision status, age group, sexual-risk behavior, HIV status, and stage of infection. A three-level conceptual framework was also developed to determine maximum epidemic impact and program efficiency through subpopulation prioritization, based on age, geography, and risk profile. In the baseline scenario, achieving 80% VMMC coverage by 2017 among males 15–49 year old, 12 VMMCs were needed per HIV infection averted (effectiveness). The cost per infection averted (cost-effectiveness) was USD $1,089 and 306,000 infections were averted. Through age-group prioritization, effectiveness ranged from 11 (20–24 age-group) to 36 (45–49 age-group); cost-effectiveness ranged from $888 (20–24 age-group) to $3,300 (45–49 age-group). Circumcising 10–14, 15–19, or 20–24 year old achieved the largest incidence rate reduction; prioritizing 15–24, 15–29, or 15–34 year old achieved the greatest program efficiency. Through geographic prioritization, effectiveness ranged from 9–12. Prioritizing Lusaka achieved the highest effectiveness. Through risk-group prioritization, prioritizing the highest risk group achieved the highest effectiveness, with only one VMMC needed per infection averted; the lowest risk group required 80 times more VMMCs.ConclusionEpidemic impact and efficiency of VMMC programs can be improved by prioritizing young males (sexually active or just before sexual debut), geographic areas with higher HIV prevalence than the national, and high sexual-risk groups.