Spatial patterns of gene expression during development
Sea urchin embryogenesis.
During development, gene regulatory networks (GRNs) control the dynamic spatial patterns in which regulatory genes are expressed. As such, GRN models can potentially reveal system-level causal relationships during the developmental process. In their Feature Article, Isabelle Peter et al. (pp. 16434–16442) transform a well-established GRN model into a predictive and dynamic Boolean computational model that computes spatial and temporal gene expression based on the regulatory logic and gene interactions for embryonic development in the sea urchin. During the initial 30 hours until the gastrula formed, the model predicted hourly expression patterns of numerous individual regulatory genes in four different spatial domains of the embryo, according to the authors, with remarkable spatial and temporal accuracy compared with direct observation. In addition, the authors used the model to perturb in silico regulatory functions and spatial patterns in the embryo and reproduced developmental abnormalities that matched experimental results. According to the authors, the study demonstrates that the adapted GRN model contains sufficient information to describe gene expression during the complex developmental process, and that the Boolean model can serve as a tool to test in silico regulatory connections and developmental perturbations. — T.J.
Parallel Alzheimer’s treatments suggest single therapeutic target
Alzheimer’s disease is characterized by an accumulation of amyloid-β (Aβ) plaques on the brain that induce progressive memory loss. Studies related to Aβ metabolism and toxicity have yielded a wide range of potential drug targets for treating the disease. Lei Wang et al. (pp. 16743–16748) used two independent research approaches—synaptic plasticity-based analysis and behavioral screening of synthetic compounds—to determine if some of these targets are better suited for drug development than others. The authors explored whether overlapping and converging effects would reveal single compounds that rescue Aβ-induced memory loss in both transgenic fruit fly and transgenic mouse models. According to the authors, two clinically available drugs and three synthetic compounds produced positive effects in behavioral tests and antagonized the Aβ oligomers-induced activation of epidermal growth factor receptor (EGFR), a signaling pathway that the authors subsequently linked to Alzheimer’s dementia. These convergent results from parallel approaches, combined with trials with Aβ-induced deficits in transgenic animals, lead the authors to conclude that EGFR is a preferred target for treating Aβ-induced memory loss. According to the authors, the findings suggest that EGFR inhibition may represent an important therapeutic target for Alzheimer’s disease in humans. — T.J.
Inherited risk of testicular cancer
Ancestral genotype controls TGCT susceptibility across multiple generations.
While testicular germ cell tumors (TGCTs) rank third in heritability among all cancers, epigenetic effects related to maternal conditions are thought to affect susceptibility as much—or more than—genomic factors. Investigating a possible molecular mechanism for these effects, Vicki Nelson et al. (pp. 16414–16415) examined the Deadend1 (Dnd1) gene that enhances TGCT susceptibility in mice, by in part interacting epigenetically with other TGCT modifier genes in previous generations. Noting that Dnd1 shares sequence similarity with Apobec1 complementation factor, a protein involved in RNA editing, the authors conducted experiments with a genetically engineered Apobec1 deficiency in TGCT-susceptible mice. The experiments, the authors report, revealed that partial loss of Apobec1 function conferred an increased TGCT risk in the paternal line that was inherited in a conventional manner. By contrast, partial loss suppressed TGCTs in the maternal line in both partially and fully deficient males, and significantly reduced TGCT risk in a transgenerational manner. The findings suggest that Apobec1 critically impacts TGCT susceptibility in both a conventional and transgenerational manner, according to the authors. — T.J.
Exploring gender bias in academic science
Female scientists may experience gender bias in academic science. ©iStockphoto.com/Kay Ransom.
Women remain underrepresented in many fields of academic science, despite increased efforts to recruit and retain women. Using a randomized, double-blind study design, Corinne Moss-Racusin et al. (pp. 16474–16479) investigated whether academic science faculty exhibit gender biases that could contribute to this disparity. The authors asked a nationwide sample of 127 biology, chemistry, and physics professors to evaluate the application materials of an undergraduate student ostensibly applying for a lab manager position. All professors received identical applications, which were randomly attributed to either a male or a female student. The authors found that the male student was more likely to be hired and offered mentoring, was rated as more competent, and was offered a higher salary than the female student with the identical credentials. This bias was independent of the faculty member’s gender, scientific discipline, age, and tenure status. Instead, the study revealed that the female student was less likely to be hired because she was viewed as less competent than the male student, according to the authors. Additional analyses revealed a preexisting subtle bias against women that undermined the faculty participants’ perceptions and treatment of the female applicant. The findings suggest that the faculty members’ bias may be unintentional, stemming from widespread cultural stereotypes about women’s competence in science, and could hinder female participation in science, the authors propose. — N.Z.
Neuronal nitric oxide initiates and maintains penile erection
Nitric oxide (NO) generated by neuronal NO synthase (nNOS) is an established mediator of penile erection. Though nNOS is closely tied to penile innervation, NO signaling is thought to initiate erection but not participate in the sustained erection required for normal sexual performance. K. Joseph Hurt et al. (pp. 16624–16629) show that cyclic adenosine monophosphate (AMP)-dependent protein kinase (PKA) phosphorylates nNOS at serine (S)1412 and mediates erectile physiology, including sustained erection. Using a specially designed antibody that selectively recognizes nNOS phosphorylated at S1412, the authors show that electrically stimulating penile innervation in rats increases S1412 phosphorylation, and that PKA inhibitors block this response. In addition, the authors found that forskolin (FSK), a drug commonly used in the laboratory to increase intracellular cyclic AMP, also activates nNOS phosphorylation. In further trials with mice, the authors report, nNOS deletion or treatment with a known NOS inhibitor prevented sustained erection, either elicited by FSK injection or augmented by FSK during electrical stimulation. Taken together, the findings strongly suggest that nNOS both initiates and helps maintain penile erection, offering a therapeutic target for treating erectile dysfunction, according to the authors. — T.J.