Volume 9 Issue 9, September 2007

Scientists are seeking permission to generate human embryonic stem cells to study disease by introducing human genetic material into an animal oocyte. This has raised ethical questions that centre on whether the entities being generated are actually human. The answer to these questions will determine how this area of research will be regulated and whether such work will be legal. The function of the extra-nuclear mitochondrial genome lies at the heart of these issues and forms the focus of this commentary.

The laboratory mouse is widely considered the model organism of choice for studying the diseases of humans, with whom they share 99% of their genes. A distinguished history of mouse genetic experimentation has been further advanced by the development of powerful new tools to manipulate the mouse genome. The recent launch of several international initiatives to analyse the function of all mouse genes through mutagenesis, molecular analysis and phenotyping underscores the utility of the mouse for translating the information stored in the human genome into increasingly accurate models of human disease.

During development, stem and progenitor cells gradually commit to differentiation pathways. Cell fate decisions are regulated by differentiation factors, which activate transcription programmes that specify lineage and differentiation status. Among these factors, the transforming growth factor (TGF)-β family is important in both lineage selection and progression of differentiation of most, if not all, cell and tissue types. There is now increasing evidence that TGF-β family proteins have the ability to redirect the differentiation of cells that either have fully differentiated or have engaged in differentiation along a particular lineage, and can thereby elicit 'transdifferentiation'. This capacity for cellular plasticity is critical for normal embryonic development, but when recapitulated in the adult it can give rise to, or contribute to, a variety of diseases. This is illustrated by the ability of TGF-β family members to redirect epithelial cells into mesenchymal differentiation and to cause switching of mesenchymal cells from one lineage to another. Hence, various pathologies in adults may be considered diseases of abnormal development and differentiation.

The Hedgehog (Hh) pathway plays central roles in animal development and stem-cell function. Defects in Hh signalling lead to birth defects and cancer in humans. The first and often genetically damaged step in this pathway is the interaction between two membrane proteins — Patched (Ptc), encoded by a tumour suppressor gene, and Smoothened (Smo), encoded by a proto-oncogene. Recent work linking Hh signalling to sterol metabolites and protein-trafficking events at the primary cilium promises to shed light on the biochemical basis of how Patched inhibits Smoothened, and to provide new avenues for cancer treatment.

During development, embryonic cells sculpt three-dimensional tissues. Although cell polarity is commonly analysed along one, and sometimes two, dimensions, this perspective illustrates how higher-order cell polarity regulates convergent extension — the coordinated cell rearrangement that produces solid tissue elongation.

The evolutionarily conserved PAR3–PAR6–aPKC–Cdc42 complex has a well-established role in cell polarity. The exact job of PAR proteins in polarity is not known, but the finding that they affect endocytosis casts new light on their function.

Most organisms, from bacteria to humans, can follow temperature gradients to an optimal temperature. Experience influences eukaryotes' preferred temperature, and, as it turns out, bacteria also adjust their temperature preference depending on growth conditions.

Toll-like receptors participate in the inflammatory response and are now shown to act in neural precursor cells to regulate adult hippocampal neurogenesis. The dialogue between inflammatory components and neural precursor cells might have important consequences for central nervous system homeostasis and repair.

With six specially-commissioned articles, the Focus on Development and Disease highlights how developmental pathways gone awry can cause disease. This focus is published in the September 2007 issue.