Biomedical subjects

Alexandra Gulacsi

Publications and source records attributed to Alexandra Gulacsi.

5 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↗

PubMed2006

Shh maintains Nkx2.1 in the MGE by a Gli3-independent mechanism.

Gamma-aminobutyric acidergic (GABAergic) interneurons perform crucial roles in cortical development and function. These roles are executed by diverse subgroups of interneurons, and dysfunction of particular subgroups may contribute to a variety of neuropsychiatric diseases. In rodents, most cortical interneurons originate in the pallidal telencephalon that also gives rise to the GABAergic neurons of the striatum and other ventral structures. In this paper, we examine the evidence for distinct origins of interneuron subgroups and then discuss the role of the homeobox gene thyroid transcription factor1 (Ttf-1 or Nkx2.1) in the specification of interneurons from the medial ganglionic eminence (MGE). Nkx2.1 is induced in the pallidal telencephalon by the action of sonic hedgehog (Shh) that antagonizes formation of the dorsalizing Gli3 repressor (Gli3R) protein. Recent evidence suggests that Shh is also required to maintain Nkx2.1 expression, and thus MGE interneuron specification, during embryonic neurogenesis. Here we provide evidence that, in contrast to the initial induction of Nkx2.1 during telencephalic patterning, the Nkx2.1 maintenance function of Shh does not require blocking the formation of the Gli3R. The plastic nature of Nkx2.1 expression during the age range of interneuron genesis suggests that factors regulating this gene can be critical determinants of the balance of excitation and inhibition in the postnatal cerebral cortex.

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

Unexpected mobility variation among individual secretory vesicles produces an apparent refractory neuropeptide pool.

Most stored neuropeptide cannot be released from nerve terminals suggesting the existence of a refractory pool of dense core vesicles (DCVs). Past fluorescence photobleaching recovery, single particle tracking and release experiments suggested that the refractory neuropeptide pool corresponds to a distinct immobile fraction of cytoplasmic DCVs. However, tracking of hundreds of individual green fluorescent protein-labeled neuropeptidergic vesicles by wide-field or evanescent-wave microscopy shows that a separate immobile fraction is not evident. Instead, the DCV diffusion coefficient (D) distribution is unusually broad and asymmetric. Furthermore, the distribution shifts with a release facilitator. This unexpected variation, which could reflect heterogeneity among vesicles or in their medium, is shown to generate the appearance of a regulated refractory neuropeptide pool.

Animals↗