Paulette A Zaki

The University of Edinburgh, Edinburgh, SCT, United Kingdom

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Publications (7)24.73 Total impact

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    ABSTRACT: Studies performed over the last decade have significantly increased our understanding of the role of Hedgehog (Hh) signalling in brain development. Here, we review the various in vitro and in vivo studies demonstrating the importance of Hh signalling for dorsoventral patterning of the telencephalon. The use of conditional knockouts has been particularly helpful in defining the spatial and temporal requirements of Hh signalling during telencephalic development. We also discuss the primary effectors of Hh signalling, the Gli family of transcription factors, and focus on Gli3, which is particularly important for telencephalic development, as reflected in the severe telencephalic phenotype of Gli3 mutant mice. The presence of some dorsoventral patterning in animals lacking both Shh and GH3 implies that, although these molecules are major players in patterning the telencephalon, other patterning factors exist.
    05/2008: pages 23-35;
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    ABSTRACT: Many cerebral cortical neurons and glia are produced by apical progenitors dividing at the ventricular surface of the embryonic dorsal telencephalon. Other neurons are produced by basal progenitor cells, which are derived from apical progenitors, dividing away from the ventricular surface. The transcription factor Pax6 is expressed in apical progenitors and is downregulated in basal progenitors, which upregulate the transcription factor Tbr2. Here we show that Pax6(-/-) cells are under-represented in the cortex of Pax6(+/+)<-->Pax6(-/-) chimeras early in corticogenesis, indicating that Pax6 is required for the production of normal numbers of cortical cells. We provide evidence that this underproduction is attributable to an early depletion of the progenitor pool caused by greater than normal proportions of newly divided cells exiting the cell cycle. We show that most progenitor cells dividing away from the ventricular surface in Pax6(-/-) embryos fail to express the transcription factor Tbr2 and that Pax6 is required cell autonomously for Tbr2 expression in the developing cortex of Pax6(+/+)<-->Pax6(-/-) chimeras. Transcription factors normally expressed ventrally in the telencephalic ganglionic eminences (Mash1, Dlx2 and Gsh2) are upregulated cell autonomously in mutant cells in the developing cortex of Pax6(+/+)<-->Pax6(-/-) chimeras; Nkx2.1, which is expressed only in the medial ganglionic eminence, is not. These data indicate that early functions of Pax6 in developing cortical cells are to repress expression of transcription factors normally found in the lateral ganglionic eminence, to prevent precocious differentiation and depletion of the progenitor pool, and to induce normal development of cortical basal progenitor cells.
    Developmental Biology 03/2007; 302(1):50-65. · 3.87 Impact Factor
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    ABSTRACT: The transcription factor Gli3 (glioma-associated oncogene homolog) is essential for normal development of the mammalian forebrain. One extreme requirement for Gli3 is at the dorsomedial telencephalon, which does not form in Gli3(Xt/Xt) mutant mice lacking functional Gli3. In this study, we analyzed expression of Gli3 in the wild-type telencephalon and observed a (high)dorsal-to-(low)ventral gradient of Gli3 expression and predominance of the cleaved form of the Gli3 protein dorsally. This graded expression correlates with the (severe)dorsal-to-(mild)ventral telencephalic phenotype observed in Gli3(Xt/Xt) mice. We characterized the abnormal joining of the telencephalon to the diencephalon and defined the medial limit of the dorsal telencephalon in Gli3(Xt/Xt) mice early in corticogenesis. Based on this analysis, we concluded that some of the abnormal expression of ventral telencephalic markers previously described as being in the dorsal telencephalon is, in fact, expression in adjacent diencephalic tissue, which expresses many of the same genes that mark the ventral telencephalon. We observed occasional cells with diencephalic character in the Foxg1 (forkhead box)-expressing Gli3(Xt/Xt) telencephalon at embryonic day 10.5, a day after the anatomical subdivision of the forebrain vesicle. Large clusters of such cells appear in the Gli3(Xt/Xt) neocortical region at later ages, when the neocortex becomes highly disorganized, forming rosettes comprising mainly neural progenitors. We propose that Gli3 is indispensable for formation of an intact telencephalic-diencephalic boundary and for preventing the abnormal positioning of diencephalic cells in the dorsal telencephalon.
    Journal of Neuroscience 10/2006; 26(36):9282-92. · 6.91 Impact Factor
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    ABSTRACT: Knowledge of the consequences of heterozygous mutations of developmentally important genes is important for understanding human genetic disorders. The Gli3 gene encodes a zinc finger transcription factor and homozygous loss-of-function mutations of Gli3 are lethal. Humans heterozygous for mutations in this gene suffer Greig cephalopolysyndactyly or Pallister-Hall syndromes, in which limb defects are prominent, and mice heterozygous for similar mutations have extra digits. Here we examined whether eye development, which is abnormal in mice lacking functional Gli3, is defective in Gli3+/- mice. We showed that Gli3 is expressed in the developing eye but that Gli3+/- mice have only very subtle eye defects. We then generated mice compound heterozygous for mutations in both Gli3 and Pax6, which encodes another developmentally important transcription factor known to be crucial for eye development. Pax6+/-; Gli3+/- eyes were compared to the eyes of wild-type, Pax6+/- or Gli3+/- siblings. They exhibited a range of abnormalities of the retina, iris, lens and cornea that was more extensive than in single Gli3+/- or Pax6+/- mutants or than would be predicted by addition of their phenotypes. These findings indicate that heterozygous mutations of Gli3 can impact on eye development. The importance of a normal Gli3 gene dosage becomes greater in the absence of a normal Pax6 gene dosage, suggesting that the two genes co-operate during eye morphogenesis.
    BMC Developmental Biology 02/2006; 6:46. · 2.73 Impact Factor
  • International Journal of Developmental Neuroscience - INT J DEV NEUROSCI. 01/2006; 24(8):556-556.
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    ABSTRACT: The transcription factor Gli3 is important for brain and limb development. Mice homozygous for a mutation in Gli3 (Gli3Xt/Xt) have severe abnormalities of telencephalic development and previous studies have suggested that aberrant cell death may contribute to the Gli3Xt/Xt phenotype. We demonstrate that telencephalic cells from embryonic Gli3Xt/Xt embryos survive better and are more resistant to death induced by cytosine arabinoside, a nucleoside analogue that induces death in neuronal progenitors and neurons, than are control counterparts in vitro. Culture medium conditioned by Gli3Xt/Xt cells is more effective at enhancing the viability of control telencephalic cells than medium conditioned by control cells, indicating that Gli3Xt/Xt cells release a factor or factors which enhance telencephalic cell viability. Gli3(Xt/Xt) cells are also more sensitive to released factors present in conditioned media. These data suggest that Gli3 plays both cell-autonomous and cell-nonautonomous roles in mediating telencephalic cell viability.
    European Journal of Neuroscience 10/2005; 22(6):1547-51. · 3.75 Impact Factor
  • Paulette A Zaki, Jane C Quinn, David J Price
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    ABSTRACT: As the telencephalon first emerges from anterior neuroectoderm, signalling molecules and transcription factors combine to specify the identity and fate of cells in each of its regions. Studies of both naturally occurring and transgenic mutant mice have identified many genes that contribute to this process. The development of telencephalon and its regions is specified by signalling molecules produced at sites both surrounding and within the telencephalon. Different parts of the telencephalon express different combinations of transcription factors that control processes including proliferation, cell fate determination and migration in order to create the unique phenotype of each region.
    Current Opinion in Genetics & Development 09/2003; 13(4):423-37. · 7.47 Impact Factor