Journal Club: Neuroscience, Chemical Biology, Human Evolution, and Developmental Biology

Graduate Division

NEUROSCIENCE: Co-expression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Willsey, A.J. et al. (State). Cell. 155(5):997-1007.

Autism spectrum disorder (ASD) has been the subject of burgeoning public and scientific interest. ASDs are a varied set of syndromes generally characterized by impaired social interaction, language difficulties and repetitive behaviors.

Initial efforts to characterize genetic causes of ASD were hampered by its heterogeneity. Through next-generation sequencing, however, several groups have identified rare mutations with relatively large effects. Although rare mutations contribute to only a minority of ASD cases, it has been hypothesized that analysis of these genes can clarify the pathogenesis of the disorder.

In this paper, the researchers used diverse human brain expression data to construct co-expression networks built around nine high-confidence ASD genes, and looked for enrichment of a separate set of probable ASD genes. They found the most significant convergence in expression in a population of cortical projection neurons in the second trimester of development.

CHEMICAL BIOLOGY: K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Ostrem, J.M.; Peters, U.; Sos, M.L.; Wells, J.A.; Shokat, K.M. Nature. doi:10.1038/nature12796

The small GTPase K-Ras is mutated in approximately 30 percent of all cancers and is frequently implicated in lung, colon, and pancreatic cancer. Years of attempts to design an effective therapy targeting this protein, however, have thus far proved fruitless.

The K-Ras mutation G12C occurs in seven percent of lung cancers. Following in the footsteps of mutant-selective therapies such as the B-Raf (V600E) inhibitor vemurafenib, the Shokat group sought to specifically target this mutant with a compound that would covalently bind to this ectopic cysteine.

In this paper, the researchers report development of a small molecule inhibitor that selectively binds K-Ras (G12C). They use in vitro assays to show that this inhibitor substantially decreases K-Ras activity by decreasing its affinity for GTP relative to GDP and by impairing binding to the enzyme target Raf. They are currently optimizing this inhibitor and investigating its therapeutic potential.

HUMAN EVOLUTION: Many human accelerated regions are developmental enhancers. Capra, J.A.; Erwin, G.D.; McKinsey, G.; Rubenstein, J.L.; Pollard, K.S. Philos Trans R Soc Lond B Biol Sci. 368:20130025.

Great apes may be our closest evolutionary relatives, but there are nevertheless obvious physical and cognitive differences between humans and chimpanzees. The genetic basis for human-specific traits remains largely unknown, though much of the difference is thought to be due to alterations in non-coding gene regulatory sequences.

Researchers analyzed conserved regions that show many changes since humans diverged from chimpanzees to develop a set of approximately 2,600 so-called human accelerated regions. Based on sequence and histone modification data, they estimated that a third of them would function as developmental enhancers.

The researchers then tested both the human and chimpanzee sequence of 29 of these regions by making transgenic mice. In five cases, there was a difference in expression pattern driven by human compared to chimpanzee sequence at embryonic day 11.5, suggesting that they merit further study as candidates for human-specific characteristics.

DEVELOPMENTAL BIOLOGY: Species-specific regulation of the cell cycle and the timing of events during craniofacial osteogenesis. Yu, J. et al. (Schneider). Dev Biol. doi:10.1016/j.ydbio.2013.11.011.

A bird’s beak tells much about its way of life and is subject to rapid evolutionary change. Previous experiments with quail-duck chimeras  have shown that the neural crest mesenchyme is the critical determinant of species-specific beak and skull development.

Earlier work has clarified the mechanism by which these cells shape the development of the skin, musculature, and connective tissue, but how it shapes the bony skeleton remained unclear.

In this paper, the researchers confirmed that transplanted quail-to-duck neural crest mesenchyme drives the faster quail-like timetable for bone development. The researchers showed these cells regulate the cell cycle. These species-specific differences in cell cycle result in differences in the timing of osteogenesis and, consequently, differences in craniofacial skeleton size.