Gli3 is required for the specification and differentiation of preplate neurons

AbstractDuring corticogenesis, the cerebral cortex develops a laminated structure which is essential for its function. Early born neurons of the preplate and its derivatives, the marginal zone (MZ) and the subplate (SP), serve as a framework during the cortical lamination process. Here, I report on defects in the generation and specification of these early born cortical neurons in extra-toes (XtJ) mice which are defective for the Gli3 zinc finger transcription factor. The Gli3 mutation dramatically disrupts early steps in the cortical lamination process. The MZ, SP and the cortical plate (CP) do not form layers but cortical neurons are arranged in clusters. These defects start to become evident at E12.5 when the cortex forms several protrusions and the ventricular zone becomes undulated. At this stage, cortical progenitor cells start to loose their apical/basal cell polarity correlating with an ectopic expression of Wnt7b in the ventricular zone. In addition, the cellular composition of the preplate is severely altered. Cajal-Retzius cells are reduced in numbers while early born Calretinin+ neurons are overproduced. These results show that multiple aspects of corticogenesis including the organization of the venticular zone, the apical/basal cell polarity of cortical progenitors and the differentiation of early born cortical neurons are affected in the Gli3 mutant

HSV-1 not only in human vestibular ganglia but also in the vestibular labyrinth

Reactivation of herpes simplex virus type 1 (HSV-1) in the vestibular ganglion (VG) is the suspected cause of vestibular neuritis (VN). Recent studies reported the presence of HSV-1 DNA not only in human VGs but also in vestibular nuclei, a finding that indicates the possibility of viral migration to the human vestibular labyrinth. Distribution of HSV-1 DNA was determined in geniculate ganglia, VGs, semicircular canals, and macula organs of 21 randomly obtained human temporal bones by nested PCR. Viral DNA was detected in 48% of the labyrinths, 62% of the VGs, and 57% of the geniculate ganglia. The potential significance of this finding is twofold: (1) Inflammation in VN could also involve the labyrinth and thereby cause acute unilateral vestibular deafferentation. (2) As benign paroxysmal positional vertigo often occurs in patients who have had VN, it could also be a sequel of viral labyrinthitis. Copyright (C) 2001 S. Karger AG, Basel

Differential requirements for Fgf3 and Fgf8 during mouse forebrain development

El pdf del artículo es la versión pre-print.Multiple Fgfs are expressed during formation and patterning of the telencephalon in vertebrates. Fgf8 has been shown to control the size of the telencephalon and the development of signaling centers in zebrafish and mouse. Next to Fgf8, Fgf3 also influences telencephalic gene expression in the zebrafish. Moreover, Fgf3 and Fgf8 have been shown to have combinatorial functions during forebrain development in this species. Here, we have examined telencephalic development in Fgf3 null mouse mutants and embryos that lack both Fgf3 and Fgf8 in their forebrain. In contrast to zebrafish, Fgf3 mutants show normal forebrain development and expression of telencephalic marker genes. Although double mutants for Fgf3 and Fgf8 show a further reduction of forebrain size no additional changes of telencephalic gene expression are observed compared with Fgf8 mutants. Therefore unlike in zebrafish, Fgf3 is not required for mouse forebrain development whereas Fgf8 has a central role during this process. © 2008 Wiley-Liss, Inc.We acknowledge the support of the Spanish Ministry of Education (BFU2007-60130), Ciberned, TerCel, and the Junta of Castilla y León to T.S and E.D-F.Peer Reviewe

Gli3 is required in Emx1+ progenitors for the development of the corpus callosum

AbstractThe corpus callosum (CC) is the largest commissure in the forebrain and mediates the transfer of sensory, motor and cognitive information between the cerebral hemispheres. During CC development, a number of strategically located glial and neuronal guidepost structures serve to guide callosal axons across the midline at the corticoseptal boundary (CSB). Correct positioning of these guideposts requires the Gli3 gene, mutations of which result in callosal defects in humans and mice. However, as Gli3 is widely expressed during critical stages of forebrain development, the precise temporal and spatial requirements for Gli3 function in callosal development remain unclear. Here, we used a conditional mouse mutant approach to inactivate Gli3 in specific regions of the developing telencephalon in order to delineate the domain(s) in which Gli3 is required for normal development of the corpus callosum. Inactivation of Gli3 in the septum or in the medial ganglionic eminence had no effect on CC formation, however Gli3 inactivation in the developing cerebral cortex led to the formation of a severely hypoplastic CC at E18.5 due to a severe disorganization of midline guideposts. Glial wedge cells translocate prematurely and Slit1/2 are ectopically expressed in the septum. These changes coincide with altered Fgf and Wnt/β-catenin signalling during CSB formation. Collectively, these data demonstrate a crucial role for Gli3 in cortical progenitors to control CC formation and indicate how defects in CSB formation affect the positioning of callosal guidepost cells

Gli3 Controls Corpus Callosum Formation by Positioning Midline Guideposts During Telencephalic Patterning

The corpus callosum (CC) represents the major forebrain commissure connecting the 2 cerebral hemispheres. Midline crossing of callosal axons is controlled by several glial and neuronal guideposts specifically located along the callosal path, but it remains unknown how these cells acquire their position. Here, we show that the Gli3 hypomorphic mouse mutant Polydactyly Nagoya (Pdn) displays agenesis of the CC and mislocation of the glial and neuronal guidepost cells. Using transplantation experiments, we demonstrate that agenesis of the CC is primarily caused by midline defects. These defects originate during telencephalic patterning and involve an up-regulation of Slit2 expression and altered Fgf and Wnt/β-catenin signaling. Mutations in sprouty1/2 which mimic the changes in these signaling pathways cause a disorganization of midline guideposts and CC agenesis. Moreover, a partial recovery of midline abnormalities in Pdn/Pdn;Slit2−/− embryos mutants confirms the functional importance of correct Slit2 expression levels for callosal development. Hence, Gli3 controlled restriction of Fgf and Wnt/β-catenin signaling and of Slit2 expression is crucial for positioning midline guideposts and callosal developmen

The mitochondrial calcium uniporter is crucial for the generation of fast cortical network rhythms

The role of the mitochondrial calcium uniporter (MCU) gene (Mcu) in cellular energy homeostasis and generation of electrical brain rhythms is widely unknown. We investigated this issue in mice and rats using Mcu-knockout and -knockdown strategies in vivo and in situ and determined the effects of these genetic manipulations on hippocampal gamma oscillations (30–70 Hz) and sharp wave-ripples. These physiological network states require precise neurotransmission between pyramidal cells and inhibitory interneurons, support spike-timing and synaptic plasticity and are associated with perception, attention and memory. Absence of the MCU resulted in (i) gamma oscillations with decreased power (by >40%) and lower synchrony, including less precise neural action potential generation (‘spiking'), (ii) sharp waves with decreased incidence (by about 22%) and decreased fast ripple frequency (by about 3%) and (iii) lack of activity-dependent pyruvate dehydrogenase dephosphorylation. However, compensatory adaptation in gene expression related to mitochondrial function and glucose metabolism was not detected. These data suggest that the neuronal MCU is crucial for the generation of network rhythms, most likely by influences on oxidative phosphorylation and perhaps by controlling cytoplasmic Ca(2+) homeostasis. This work contributes to an increased understanding of mitochondrial Ca(2+) uptake in cortical information processing underlying cognition and behaviour