The argument for diversifying the NIH grant portfolio

The United States has been a leader in biomedical science for decades, in large part because of the strategy used by the National Institutes of Health (NIH) to invest its budgetary portfolio. They identified talented young scientists from each generation and gave them the resources they needed to initiate and maintain strong research programs. However, recently this investment has become less diversified, with a larger fraction of grant dollars in the hands of a smaller fraction of researchers. This threatens the future of our field, as many productive early and midcareer scientists are facing having to close their labs. NIH and others have studied this problem, gathering data that suggest that over a certain level of funding to an individual investigator, there are diminishing returns in scientific output. Here I review these data and examine the issues that led NIH to propose and then reverse a cap on funding to individual investigators, the Grant Support Index. I consider other proposed solutions, and call on all in the field to examine whether the status quo is acceptable, and if not, urge them to propose and advocate for concrete alternatives

Wnt signaling: Moving in a new direction

Evidence supporting the postulated role of a Wnt ligand in the establishment of planar cell polarity has been elusive, but recent studies show that the movement of epithelial cells during vertebrate gastrulation or Drosophila dorsal closure depends on both a Wnt ligand and the planar cell polarity pathway

Wnt signaling: Moving in a new direction

Evidence supporting the postulated role of a Wnt ligand in the establishment of planar cell polarity has been elusive, but recent studies show that the movement of epithelial cells during vertebrate gastrulation or Drosophila dorsal closure depends on both a Wnt ligand and the planar cell polarity pathway

Wnt signaling: The Naked truth?

Frizzled receptors can activate two alternative signal transduction pathways: the canonical Wnt pathway or the planar cell polarity pathway. Recent studies of the Naked cuticle protein suggest a mechanism for the inactivation of the canonical pathway and concomitant activation of the planar cell polarity pathway

Cell Biology: A Tense but Good Day for Actin at Cell–Cell Junctions

SummaryCells have evolved an elegant tuning mechanism to maintain tissue integrity, in which increasing mechanical tension stimulates actin assembly at cell–cell junctions. The mechanosensitive junctional protein α-catenin acts through vinculin and Ena/VASP proteins to reinforce the cell against mechanical stress

Traffic control: p120-catenin acts as a gatekeeper to control the fate of classical cadherins in mammalian cells

Proteins of the p120 family have been implicated in the regulation of cadherin-based cell adhesion, but their relative importance in this process and their mechanism of action have remained less clear. Three papers in this issue suggest that p120 plays a key role in maintaining normal levels of cadherin in mammalian cells, and that it may do so by regulating cadherin trafficking (Chen et al., 2003; Davis et al., 2003; Xiao et al., 2003)

Adherens junction-dependent and -independent steps in the establishment of epithelial cell polarity in Drosophila

Adherens junctions (AJs) are thought to be key landmarks for establishing epithelial cell polarity, but the origin of epithelial polarity in Drosophila remains unclear. Thus, we examined epithelial polarity establishment during early Drosophila development. We found apical accumulation of both Drosophila E-Cadherin (DE-Cad) and the apical cue Bazooka (Baz) as cells first form. Mutant analyses revealed that apical Baz accumulations can be established in the absence of AJs, whereas assembly of apical DE-Cad complexes requires Baz. Thus, Baz acts upstream of AJs during epithelial polarity establishment. During gastrulation the absence of AJs results in widespread cell dissociation and depolarization. Some epithelial structures are retained, however. These structures maintain apical Baz, accumulate apical Crumbs, and organize polarized cytoskeletons, but display abnormal cell morphology and fail to segregate the basolateral cue Discs large from the apical domain. Thus, although epithelial polarity develops in the absence of AJs, AJs play specific roles in maintaining epithelial architecture and segregating basolateral cues

What your PI forgot to tell you: why you actually might want a job running a research lab

A PhD in biomedical science and the critical thinking skills that it provides can open the door to many different careers. The current popular scientific press and blogosphere too often portray the job of a research-intensive faculty member and principal investigator (PI) as both unattainable and undesirable. We want to make sure our trainees include our own career path among their options, as for each of us it has been a fantastic, family-friendly, and highly impactful career

A role for a novel centrosome cycle in asymmetric cell division

Tissue stem cells play a key role in tissue maintenance. Drosophila melanogaster central brain neuroblasts are excellent models for stem cell asymmetric division. Earlier work showed that their mitotic spindle orientation is established before spindle formation. We investigated the mechanism by which this occurs, revealing a novel centrosome cycle. In interphase, the two centrioles separate, but only one is active, retaining pericentriolar material and forming a “dominant centrosome.” This centrosome acts as a microtubule organizing center (MTOC) and remains stationary, forming one pole of the future spindle. The second centriole is inactive and moves to the opposite side of the cell before being activated as a centrosome/MTOC. This is accompanied by asymmetric localization of Polo kinase, a key centrosome regulator. Disruption of centrosomes disrupts the high fidelity of asymmetric division. We propose a two-step mechanism to ensure faithful spindle positioning: the novel centrosome cycle produces a single interphase MTOC, coarsely aligning the spindle, and spindle–cortex interactions refine this alignment

The positioning and segregation of apical cues during epithelial polarity establishment in Drosophila

Cell polarity is critical for epithelial structure and function. Adherens junctions (AJs) often direct this polarity, but we previously found that Bazooka (Baz) acts upstream of AJs as epithelial polarity is first established in Drosophila. This prompted us to ask how Baz is positioned and how downstream polarity is elaborated. Surprisingly, we found that Baz localizes to an apical domain below its typical binding partners atypical protein kinase C (aPKC) and partitioning defective (PAR)-6 as the Drosophila epithelium first forms. In fact, Baz positioning is independent of aPKC and PAR-6 relying instead on cytoskeletal cues, including an apical scaffold and dynein-mediated basal-to-apical transport. AJ assembly is closely coupled to Baz positioning, whereas aPKC and PAR-6 are positioned separately. This forms a stratified apical domain with Baz and AJs localizing basal to aPKC and PAR-6, and we identify specific mechanisms that keep these proteins apart. These results reveal key steps in the assembly of the apical domain in Drosophila