There's a long, long trail a-winding: the complexities of GM foods regulation, a cautionary tale from the UK

The evolution of the regulatory process for genetically modified (GM) food in the United Kingdom is reviewed from its formal inception in 1988 to the present, drawing out lessons which have been learned from a series of cases brought to the committee for approval. The unexpected but highly professional anti-GM campaign is described, and issues regarding public perceptions of risk are discussed. Recent failures to find a consensus solution in the United Kingdom are described, and a proposal is made for a way forward.     

Pax3/7BP is a Pax7- and Pax3-binding protein that regulates the proliferation of muscle precursor cells by an epigenetic mechanism

In mouse skeletal muscles, Pax7 uniquely marks muscle satellite cells and plays some important yet unknown functions at the perinatal stage. To elucidate its in vivo functions, we initiated a yeast two-hybrid screening to look for Pax7-interacting proteins and identified a previously uncharacterized Pax7- and Pax3-binding protein (Pax3/7BP). Pax3/7BP is a ubiquitously expressed nuclear protein, enriched in Pax7+ muscle precursor cells (MPCs), and serves as an indispensable adaptor for Pax7 to recruit the histone 3 lysine 4 (H3K4) methyltransferase (HMT) complex by bridging Pax7 and Wdr5. Knockdown of Pax3/7BP abolished the Pax3/7-associated H3K4 HMT activity and inhibited the proliferation of Pax7+ MPCs from young mice both in culture and in vivo. Id3 and Cdc20 were direct target genes of Pax7 and Pax3/7BP involved in the proliferation of Pax7+ MPCs. Collectively, our work establishes Pax3/7BP as an essential adaptor linking Pax3/7 with the H3K4 HMT to regulate the proliferation of MPCs.     

Pax3 and Pax7 have distinct and overlapping functions in adult muscle progenitor cells

The growth and repair of skeletal muscle after birth depends on satellite cells that are characterized by the expression of Pax7. We show that Pax3, the paralogue of Pax7, is also present in both quiescent and activated satellite cells in many skeletal muscles. Dominant-negative forms of both Pax3 and -7 repress MyoD, but do not interfere with the expression of the other myogenic determination factor, Myf5, which, together with Pax3/7, regulates the myogenic differentiation of these cells. In Pax7 mutants, satellite cells are progressively lost in both Pax3-expressing and -nonexpressing muscles. We show that this is caused by satellite cell death, with effects on the cell cycle. Manipulation of the dominant-negative forms of these factors in satellite cell cultures demonstrates that Pax3 cannot replace the antiapoptotic function of Pax7. These findings underline the importance of cell survival in controlling the stem cell populations of adult tissues and demonstrate a role for upstream factors in this context.     

Properties of the human long and short isoforms of the uncoupling protein-3 expressed in yeast cells

Two splice variants of the human uncoupling protein-3 (UCP3L and UCP3S) are highly expressed in skeletal muscle. The properties of UCP3L and S have been compared to those of UCP1 in a heterologous yeast expression system under the control of the galactose promoter. Both UCP3 isoforms were found to strongly impair the coupling efficiency of respiring cells thus resulting in increased thermogenesis. The uncoupling properties of both UCP3L and S could be clearly demonstrated also in isolated yeast mitochondria both in terms of coupled respiration and in the capacity to polarize the inner membrane in conditions of limited substrate availability. Contrary to what was observed with mitochondria containing UCP1, millimolar GDP and ATP had little if any effect on the uncoupling activity of UCP3. A very marked uncoupling of whole cells and isolated mitochondria was observed at very low expression levels of UCP3S indicating that the short isoform is more active than the long one.     

Constitutive Notch activation upregulates Pax7 and promotes the self-renewal of skeletal muscle satellite cells

Notch signaling is a conserved cell fate regulator during development and postnatal tissue regeneration. Using skeletal muscle satellite cells as a model and through myogenic cell lineage-specific NICD(OE) (overexpression of constitutively activated Notch 1 intracellular domain), here we investigate how Notch signaling regulates the cell fate choice of muscle stem cells. We show that in addition to inhibiting MyoD and myogenic differentiation, NICD(OE) upregulates Pax7 and promotes the self-renewal of satellite cell-derived primary myoblasts in culture. Using MyoD(-/-) myoblasts, we further show that NICD(OE) upregulates Pax7 independently of MyoD inhibition. In striking contrast to previous observations, NICD(OE) also inhibits S-phase entry and Ki67 expression and thus reduces the proliferation of primary myoblasts. Overexpression of canonical Notch target genes mimics the inhibitory effects of NICD(OE) on MyoD and Ki67 but not the stimulatory effect on Pax7. Instead, NICD regulates Pax7 through interaction with RBP-Jκ, which binds to two consensus sites upstream of the Pax7 gene. Importantly, satellite cell-specific NICD(OE) results in impaired regeneration of skeletal muscles along with increased Pax7(+) mononuclear cells. Our results establish a role of Notch signaling in actively promoting the self-renewal of muscle stem cells through direct regulation of Pax7.     

The long and short of it

It can take twice as long to get a PhD in biomedical sciences in the US as it does in other countries such as the UK and Australia. Are US PhDs worth more, or are there advantages to a speedier system?     

The long and short of siRNAs

A recent work identifies a distinct class of siRNAs derived from transgenes and endogenous retroelements in plants (Hamilton et al., 2002). This class has slower electrophoretic mobility than previously characterized siRNAs and may play an important role in transgene-induced systemic silencing and in methylation of endogenous retroelement DNA.     

Plant peptide hormones: The long and the short of it

A polypeptide from tobacco has been found to be processed into multiple functional peptides, each with independent hormone-like activities. This adds to a growing set of small peptides known to function as signal molecules in plants.     

Motion: the long and short of it

Several authors have proposed that motion is analyzed by two separate processes: short-range and long-range. We claim that the differences between short-range and long-range motion phenomena are a direct consequence of the stimuli used in the two paradigms and are not evidence for the existence of two qualitatively different motion processes. We propose that a single style of motion analysis, similar to the well known Reichardt and Marr-Ullman motion detectors, underlies all motion phenomena. Although there are different detectors of this type specialized for different visual attributes (namely first-order and second-order stimuli), they all share the same mode of operation. We review the studies of second-order motion stimuli to show that they share the basic phenomena observed for first-order stimuli. The similarity across stimulus types suggests, not parallel streams of motion extraction, one short-range and passive and the other long-range and intelligent, but a concatenation of a common mode of initial motion extraction followed by a general inference process.     

Pax7 reveals a greater frequency and concentration of satellite cells at the ends of growing skeletal muscle fibers.

The main sites of longitudinal growth in skeletal muscle are the ends of the fibers. This study tests the hypothesis that satellite cells (SCs) are at a greater frequency (#SC nuclei/all nuclei within basal laminae) and concentration (closer together) within growing fiber ends of posthatch chicken pectoralis. SCs were localized by their Pax7 expression, and fiber ends were identified by their retention of neonatal myosin heavy chains and small cross-sectional profiles. Whereas SC frequency decreased from about 20% at 9 days posthatch to <5% at 115 days, fiber ends retained a frequency of approximately 16%. Calculated mean area of sarcolemma per SC revealed higher concentrations of SCs at fiber ends. There was also a strong inverse correlation between SC frequency and fiber profile cross-sectional size throughout development. This study suggests that SCs at fiber ends play a key role in the longitudinal growth of muscle fibers, and that fiber profile size may impact SC distribution.     

Mhox and vertebrate skeletogenesis: The long and the short of it

The development of the vertebrate skeleton is under complex genetic control, and good progress is being made towards identifying the genes responsible. A recent paper⁽¹⁾ contributes to this progress by describing transgenic mice in which the homeobox-containing MHox gene has been disrupted. MHox(?/?) mice have a range of skeletal defects, involving loss or shortening of structures in the skull, face and limb. Puzzling features of the MHox(?/?) mutation, which has similar effects on bones with very different embryological origins and yet spares other bones completely, may hold clues to the mechanisms that shape the skeleton. MHox(?/?) mice, used in conjunction with other skeletal mutants, will be important tools for exploring these mechanisms further.