Biomedical subjects

Laura Lillien

Publications and source records attributed to Laura Lillien.

6 recordsLinked to original sources

PubMed2006

Environmental signals elicit multiple responses in dorsal telencephalic progenitors by threshold-dependent mechanisms.

Environmental signals including epidermal growth factor family members, Shh, fibroblast growth factor, and bone morphogenetic protein (BMP) can affect multiple processes during the development of the central nervous system, raising questions about the mechanisms that determine how these pleiotropic signals are interpreted to elicit appropriate responses at specific times and locations. Here we address the idea that different thresholds of stimulation determine how progenitors in the dorsal telencephalon interpret these signals. One mechanism for achieving different thresholds of signaling is illustrated by the developmental increase in the level of epidermal growth factor receptor (EGFR) expression among a subset of progenitors in the late embryonic telencephalon. Another mechanism is illustrated by the antagonistic interaction of BMP with Shh, which can influence EGFR expression and neuron subtype choice. We focus on the similarities and differences in the control of these responses and address the possibility that the gamma-aminobutyric acidergic neuron specification might be linked to progenitor expression of a higher level of EGFRs.

Adaptation, Physiological↗

PubMed2004

Attraction or repulsion: a matter of individual taste?

Cell migration along the correct paths is critical to normal organogenesis and tissue repair, and goes awry in tumor dissemination. Understanding the molecular cues that control such migration would provide opportunities to control these events. Recent findings in Drosophila highlight the role of the epidermal growth factor receptor (EGFR) in chemotaxis and pathfinding during development. These studies, and others performed in vertebrates, support a central role for EGFR-mediated chemotaxis. However, the signal or signals that then enable cells to further migrate independently of this chemotactic effect are not known. Three possible scenarios are discussed: that EGFR signaling sensitizes cells to new cues, that EGFR signaling is altered so that the cell responds predominantly to other motility signals that are now "unblinded," and that EGFR signaling still provides the motile signal but in a chemokinetic manner with matrix components providing the directionality. There are precedents for all three scenarios, but which one proves true will define the window of opportunity for regulating cell migration.

Animals↗

PubMed2004

Akt-1 expression level regulates CNS precursors.

Although most cells in the embryonic mouse cortex express the serine-threonine kinase Akt-1, a small population of progenitors expresses Akt-1 protein at a higher level. To determine the functional significance of this difference, we used a retrovirus to increase Akt-1 expression in cortical progenitors. Increased Akt expression enhanced Akt activation after growth factor stimulation of progenitors. In vivo, it promoted retention in progenitor layers, the ventricular zone and subventricular zone. In vitro, it enhanced proliferation and survival, but did not impair migration. Moreover, it increased the proportion of stem cells, defined by a self-renewal assay. These effects did not depend on the Akt substrate p21(Cip1). In contrast, rapamycin, an inhibitor of mTOR (mammalian target of rapamycin), altered effects of elevated Akt-1 selectively: it eliminated the increase in stem cells and reduced the proliferative response, but had no effect on survival. The ability of elevated Akt-1 to increase the self-renewing population therefore depends on a rapamycin-sensitive mechanism (presumably inhibition of mTOR activity) but not on p21(Cip1), and can be distinguished from its effects on the proliferation and survival of other types of progenitors. Our findings suggest that expression of a high level of Akt-1 by a subpopulation of cortical progenitors biases their responses to extrinsic signals to increase their survival, proliferation, and/or self-renewal. Heterogeneity in Akt-1 level among progenitors could therefore allow cells that share a microenvironment to respond differently to the same extrinsic signals.

Animals↗

PubMed2003

Sonic hedgehog and bone morphogenetic protein regulate interneuron development from dorsal telencephalic progenitors in vitro.

Cortical progenitors are competent to produce interneurons, but do not generate large numbers of interneurons in vivo under normal circumstances. This could reflect the absence of an inductive signal in the environment of the dorsal telencephalon and/or the presence of an inhibitory signal. To determine whether either or both mechanisms regulate interneuron generation, progenitors in dorsomedial and dorsolateral wall explants of mouse telencephalon were marked with a retrovirus and cultured under several conditions. When cultured separately, progenitors in dorsomedial wall explants produced fewer GABAergic interneurons than progenitors in dorsolateral wall explants. When cocultured with ventral telencephalic cells, however, dorsomedial wall progenitors produced more GABAergic interneurons than in dorsomedial wall explants alone. The inductive effect of ventral telencephalon depended on sonic hedgehog (Shh) and could be mimicked by exogenous Shh. In contrast, exogenous bone morphogenetic protein 4 (BMP4) reduced the production of interneurons in dorsolateral wall explants and inhibited the induction by exogenous Shh. Moreover, inhibiting BMP signaling in dorsomedial wall progenitors with a dominant-negative BMP receptor Ib (dnBMPIb) virus increased their production of interneurons, even if Shh was blocked. Shh and dnBMPRIb increased proliferation and the generation of interneurons, but FGF2 did not induce interneurons, although it increased proliferation. This suggests that proliferation per se does not control the production of interneurons. Our findings suggest that the generation of interneurons by dorsal telencephalic progenitors is normally limited by excess levels of BMPs. Shh may promote the generation of interneurons by antagonizing BMP, but may not be required directly for the generation of interneurons.

Animals↗

PubMed2003

Wnt regulation of progenitor maturation in the cortex depends on Shh or fibroblast growth factor 2.

In the embryonic mouse cerebral cortex, progenitors in the ventricular zone (VZ) undergo a developmental change between embryonic day 13 (E13) and E15. This results in the generation of a secondary proliferative population and the appearance of a second germinal layer, the subventricular zone (SVZ). We have shown previously that bone morphogenetic proteins (BMPs) and fibroblast growth factor 2 (FGF2) act antagonistically to regulate the development of a subset of SVZ progenitors that normally express a high level of epidermal growth factor (EGF) receptors and divide in response to EGF. In the present study, we show that Wnt 7a, Wnt 7b, and Sonic hedgehog (Shh) promote progenitor maturation in explant cultures, as reported for FGF2. Wnts 7a and 7b also stimulate the proliferation of neurogenic progenitors and increase the number of cells that can generate primary neurospheres. To determine whether Wnts, FGF2, and Shh act independently or in a common pathway, each factor was inhibited in cortical explants. This revealed that endogenous Wnts, FGF2, and Shh normally contribute to progenitor maturation. Moreover, Wnt 7a depends on FGF2 or Shh to promote maturation but not proliferation. Maturation induced by blocking BMPs also depends on Shh. In contrast, FGF2 promotes maturation by a Shh-independent mechanism. In vivo, progenitors infected with a Wnt 7a retrovirus at E10.5 were found preferentially in the SVZ at E16.5. These findings suggest that Wnts depend on Shh or FGF2 to promote progenitor maturation to an SVZ state in the embryonic cortex.

Animals↗

PubMed2003

Epidermal growth factor receptors control competence to interpret leukemia inhibitory factor as an astrocyte inducer in developing cortex.

Cortical progenitors begin to interpret leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP) as astrocyte-inducing signals during late embryonic cortical development, coincident with an increase in their expression of epidermal growth factor receptors (EGFRs). To determine whether the developmental change in EGFRs regulates the change in responsiveness to LIF and BMP, we analyzed cortical progenitors induced to express EGFRs prematurely and progenitors from late embryonic EGFR-null cortex. Premature elevation of EGFRs conferred premature competence to interpret LIF, but not BMP, as an astrocyte-inducing signal. EGFR-null progenitors from late embryonic cortex did not interpret LIF as an astrocyte-inducing signal but responded to BMP4. LIF responsiveness in EGFR-null cells was rescued by the addition of EGFRs but not by the stimulation of fibroblast growth factor receptors. Astrocyte differentiation induced by LIF depends on signal transducer and activator of transcription 3 (STAT3). We show that the level of STAT3 increases during late embryonic development in a subset of progenitors. EGFRs regulate this change in STAT3 and increase STAT3 phosphorylation in response to LIF. Increasing STAT3 prematurely with a retrovirus also increased the phosphorylation of STAT3 by LIF. In contrast to the finding with EGFRs, however, increasing STAT3 did not cause LIF to induce astrocytes, although it reduced expression of the neurogenic factor PAX6 (paired box gene 6 ). Our findings show that developmental changes in EGFRs regulate the competence of progenitors to interpret LIF as an astrocyte-inducing signal. EGFRs elevate STAT3 expression and increase its phosphorylation by LIF, but this is not sufficient to change LIF responsiveness to astrocyte induction, suggesting that EGFRs also regulate LIF responsiveness downstream of STAT3.

Animals↗