Biomedical subjects

L Lillien

Publications and source records attributed to L Lillien.

14 recordsLinked to original sources

PubMed2001

EGFRs mediate chemotactic migration in the developing telencephalon.

Epidermal growth factor receptors (EGFRs) have been implicated in the control of migration in the telencephalon, but the mechanism underlying their contribution is unclear. We show that expression of a threshold level of EGFRs confers chemotactic competence in stem cells, neurons and astrocytes in cortical explants. This level of receptor expression is normally achieved by a subpopulation of cells during mid-embryonic development. Cells that express high levels of EGFR are located in migration pathways, including the tangential pathway to the olfactory bulb via the rostral migratory stream (RMS), the lateral cortical stream (LCS) leading to ventrolateral cortex and the radial pathway from proliferative zones to cortical plate. The targets of these pathways express the ligands HB-EGF and/or TGFalpha. To test the idea that EGFRs mediate chemotactic migration these pathways, we increased the size of the population of cells expressing threshold levels of EGFRs in vivo by viral transduction. Our results suggest that EGFRs mediate migration radially to the cortical plate and ventrolaterally in the LCS, but not tangentially in the RMS. Within the bulb, however, EGFRs also mediate radial migration. Our findings suggest that developmental changes in EGFR expression, together with changes in ligand expression regulate the migration of specific populations of cells in the telencephalon by a chemoattractive mechanism.

Animals↗

PubMed2000

Mechanisms of progenitor maturation are conserved in the striatum and cortex.

We recently reported that developmental changes in the expression of epidermal growth factor receptors (EGFRs) by cortical progenitor cells regulate their fate and migration. Higher levels of EGFRs are expressed by later embryonic progenitor cells and are required for several responses to EGF family ligands, including astrocyte differentiation and migration. Progenitor cells in the ganglionic eminence (GE), the forerunner of the striatum, also exhibit a developmental increase in EGFR expression. The striatum differs from the cortex in several respects, including cytoarchitecture, the timing of changes in EGFRs, and the level of transforming growth factor-alpha (TGFalpha) expression. To determine whether signaling mediated by EGFRs in GE progenitors regulates their fate and migration as observed in cortex, we used a retrovirus to increase EGFR expression in embryonic GE progenitor cells prematurely. As in cortex, premature elevation of EGFRs promoted the departure of GE progenitors from the ventricular zone and their differentiation into astrocytes. Settling patterns of infected cells in the striatum, however, differed from the patterns observed in cortex. In addition, the extent of premature astrocyte differentiation reached similar levels in striatal cells, even in the presence of greater endogenous TGFalpha. These findings suggest that additional factors play an important role in modulating EGFR-mediated changes in cell fate. Together with previous studies in cortex, these observations in the striatum indicate that a conserved mechanism involving developmental changes in EGFR expression regulates cell fate and the timing of migration.

Animals↗

PubMed2000

BMP and FGF regulate the development of EGF-responsive neural progenitor cells.

Temporal changes in progenitor cell responses to extrinsic signals play an important role in development, but little is known about the mechanisms that determine how these changes occur. In the rodent CNS, expression of epidermal growth factor receptors (EGFRs) increases during embryonic development, conferring mitotic responsiveness to EGF among multipotent stem cells. Here we show that cell-cell signaling controls this change. Whereas EGF-responsive stem cells develop on schedule in explant and aggregate cultures of embryonic cortex, co-culture with younger cortical cells delays their development. Exogenous BMP4 mimics the effect of younger cells, reversibly inhibiting changes in EGFR expression and responsiveness. Moreover, blocking endogenous BMP receptors in progenitors with a virus transducing dnBMPR1B accelerates changes in EGFR signaling. This involves a non-cell-autonomous mechanism, suggesting that BMP negatively regulates signal(s) that promote the development of EGF-responsive stem cells. FGF2 is a good candidate for such a signal, as we find that it antagonizes the inhibitory effects of younger cortical cells and exogenous BMP4. These findings suggest that a balance between antagonistic extrinsic signals regulates temporal changes in an intrinsic property of neural progenitor cells.

Animals↗

PubMed1998

Progenitor cells: what do they know and when do they know it?

In the cerebral cortex, cell-fate specification and migration depend on both extrinsic and intrinsic regulation, but recent studies raise the possibility that much of the information needed to generate distinct cell types and specific migratory patterns is intrinsic to progenitor cells at early stages of development.

Animals↗

PubMed1998

Changes in epidermal growth factor receptor expression and competence to generate glia regulate timing and choice of differentiation in the retina.

Previous studies demonstrated that the level of epidermal growth factor receptors (EGF-Rs) expressed by progenitor cells in the newborn (P0) rat retina was limiting for the generation of Muller glial cells but not for proliferation. To determine whether EGF-R signaling biases cells to generate a specific cell type or regulates more general processes during progenitor cell development, we have introduced extra copies of the EGF-R into progenitor cells at earlier stages (E15 and E18), when different cell types are produced. We show that progenitor cells in early embryonic retina (E15) normally express lower levels of EGF-Rs than progenitor cells in later retina (E18 and P0). Whereas lower levels of stimulation of endogenous and virally transduced EGF-Rs enhanced proliferation, higher levels reduced proliferation, resulting in premature differentiation. At E15, very few EGF-R-Infected progenitor cells differentiated prematurely into Muller glial cells, unlike E18 and P0 cells, even when they were exposed to an older retinal environment. Higher levels of EGF-R-mediated signaling alone therefore do not specify a glial fate, indicating that competence to generate glia is temporally regulated by additional mechanisms. The differences in EGF-R expression observed among retinal progenitor cells at distinct developmental stages may instead help to define signaling thresholds which delay or accelerate their differentiation.

3T3 Cells↗

PubMed1998

Neural progenitors and stem cells: mechanisms of progenitor heterogeneity.

Heterogeneity among progenitor cells in the vertebrate nervous system has been documented with increasing frequency over the past few years. It has become clear that differences in progenitor cells help to determine when and how they respond to environmental signals. More recent studies have begun to elucidate the molecular basis of the differences in progenitor cell subpopulations that control their developmental potential and responsiveness to environmental signals.

Animals↗

PubMed1997

Neural development: instructions for neural diversity.

Extracellular signals that can influence the fate of multipotent progenitor cells have been described in recent studies of the vertebrate nervous system, emphasizing the contribution of instructive mechanisms to the generation of cellular diversity.

Animals↗

PubMed1997

Response diversity and the timing of progenitor cell maturation are regulated by developmental changes in EGFR expression in the cortex.

Early cortical progenitor cells of the ventricular zone (VZ) differ from later progenitor cells of the subventricular zone (SVZ) in cell-type generation and their level of epidermal growth factor receptors (EGFRs). To determine whether differences in their behavior are causally related to EGFR number/density, we introduced extra EGFRs into VZ cells with a retrovirus in vivo and in vitro. This results in premature expression of traits characteristic of late SVZ progenitor cells, including migration patterns, differentiation into astrocytes, and proliferation of multipotential cells to form spheres. The choice between proliferation and differentiation depends on ligand concentration and progenitor cell age and may reflect different thresholds of stimulation. The level of EGFRs expressed by progenitor cells in the cortex may therefore contribute to the timing of their maturation and choice of response to pleiotropic environmental signals.

Animals↗

PubMed1997

Signaling pathways that regulate specification of neurons in developing cerebral cortex.

The expression of the limbic system-associated membrane protein (LAMP), a marker of specific functional regions of the cerebral cortex, has been used to determine the environmental signals that regulate cortical regionalization. Transplant and cell culture studies have shown previously that the fate of precursor cells, based on LAMP expression, is amenable to regulation by exposure to novel environmental stimuli. This has been demonstrated in vitro to be dependent upon exposure to transforming factor-alpha and collagen type IV. Results following exposure to the inductive signals for a specific duration indicate a cell cycle dependence on the decision to become a limbic or nonlimbic cortical neuron. It appears, therefore, that areal and laminar fates are both influenced by mechanisms that specify commitment early in cortical development.

Animals↗

PubMed1997

Mechanisms specifying area fate in cortex include cell-cycle-dependent decisions and the capacity of progenitors to express phenotype memory.

Progenitor cells in the early developing cerebral cortex produce neurons destined for discrete functional areas in response to specific inductive signals. Using lineage analysis, we show that cortical progenitor cells at different fetal ages retain the memory of an area-specific inductive signal received in vivo, even though they may pass through as many as two cell cycles in the absence of the signal in culture. When exposed to inductive signals in vitro, only those progenitors that progress through at least one complete cell cycle alter their areal phenotype. Our findings suggest that induction of an areal phenotype is linealy inherited, with the phenotype specified prior to the final cell cycle.

Animals↗

PubMed1995

Changes in retinal cell fate induced by overexpression of EGF receptor.

The differentiation of multipotential progenitor cells in the vertebrate retina into photoreceptors, neurons and glial cells is regulated in part by cell-cell signalling. Transforming growth factor (TGF)-alpha is one of the extracellular signals implicated in the control of several aspects of retinal development, including proliferation and cell fate. The way cells interpret pleiotropic signals such as TGF-alpha is influenced by the level of expression of epidermal growth factor receptor (EGF-R) in some cell lines. To address the influence of receptor level on responses of retinal progenitor cells to TGF-alpha, additional copies of EGF-Rs were introduced in vitro and in vivo with a retrovirus. Normally in vitro, low concentrations of TGF-alpha stimulated proliferation whereas high concentrations biased choice of cell fate, inhibiting differentiation into rod photoreceptors while promoting differentiation into Müller glial cells. We report here that introduction of extra EGF-Rs into progenitor cells in vitro reduced the concentration of TGF-alpha required for changes in rod and Müller cell differentiation but did not enhance proliferation. Introduction of extra EGF-Rs in vivo increased the proportion of clones that contained Müller glial cells, suggesting that receptor level is normally limiting. These findings demonstrate that responsiveness to extracellular signals during development can be modulated by the introduction of additional receptors, and suggest that the level of expression of receptors for these signals contributes to the regulation of cell fate.

Animals↗

PubMed1994

Neurogenesis in the vertebrate retina.

Many studies concerned with the control of neurogenesis in the retina, as well as other parts of the nervous system, impose the dichotomy of lineage restrictions versus environmental regulation on the design and interpretation of experiments. Recent work on retinal development has focused primarily on "environmental regulation," and this article will review some observations from these studies that provide clues about signals and mechanisms that control proliferation and cell type determination in the retina. Although still at an early stage, these studies already indicate that regulatory signals are not easily categorized as affecting only proliferation or differentiation, but are instead pleiotropic. Interpretation of these findings will be considered in terms of recent work in other systems, which further demonstrates that signals and regulatory mechanisms cannot be classified so simplistically and which suggests that polarizing regulatory mechanisms in terms of lineage restrictions and environmental regulation underestimates the interplay between these types of mechanisms.

Aging↗

PubMed1992

Control of photoreceptor development.

Recent studies of cell type determination in the vertebrate retina suggest that rod photoreceptor development involves interactions among cells that are mediated, at least in part, by temporally regulated diffusible signals. In this review the strategies used to generate rods in the vertebrate retina are compared with those described for photoreceptor development in the Drosophila retina.

Animals↗

PubMed1992

Control of proliferation in the retina: temporal changes in responsiveness to FGF and TGF alpha.

Proliferation in the rat retina, as in other parts of the nervous system, occurs during a restricted period of development. In addition to regulating cell number, the mechanisms that control proliferation influence the patterning of tissues, and may affect the determination of cell type. To begin to determine how proliferation is controlled, several growth factors found in the retina were tested for effects on progenitor cell division in culture. Proliferation was enhanced by TGF alpha, bFGF and aFGF, and many of the dividing cells later differentiated into cells with the antigenic phenotypes of retinal neurons and glial cells. The mitotic response of retinal cells to these factors changed during development: progenitor cells from younger retinas (embryonic day 15 to 18; E15-E18) were more responsive to FGF's, while progenitor cells from older retinas (greater than E20) were more responsive to TGF alpha. Progenitor cells stopped dividing in vitro, even when treated with excess mitogen. These observations suggest that proliferation in the retina may be stimulated by multiple mitogenic signals provided by TGF alpha, FGF, or related factors, and that proliferation is not controlled by limiting concentrations of mitogen alone. Rather, these data demonstrate that retinal cells change during development in their responsiveness to mitogenic signals. Such changes may contribute to the regulation of proliferation.

Animals↗