The temporal and spatial expression pattern of the LGI1 epilepsy predisposition gene during mouse embryonic cranial development
© Silva et al; licensee BioMed Central Ltd. 2011
Received: 31 December 2010
Accepted: 13 May 2011
Published: 13 May 2011
Mutations in the LGI1 gene predispose to a rare, hereditary form of temporal epilepsy. Currently, little is known about the temporal and spatial expression pattern of Lgi1 during normal embryogenesis and so to define this more clearly we used a transgenic mouse line that expresses GFP under the control of Lgi1 cis-regulatory elements.
During embryonic brain growth, high levels of Lgi1 expression were found in the surface ectoderm, the neuroepithelium, mesenchymal connective tissue, hippocampus, and sensory organs, such as eye, tongue, and the olfactory bulb. Lgi1 was also found in the cranial nerve nuclei and ganglia, such as vestibular, trigeminal, and dorsal ganglia. Expression of Lgi1 followed an orchestrated pattern during mouse development becoming more subdued in areas of the neocortex of the mid- and hind-brain in early postnatal animals, although high expression levels were retained in the choroid plexus and hippocampus. In late postnatal stages, Lgi1 expression continued to be detected in many areas in the brain including, hippocampus, paraventricular thalamic nuclei, inferior colliculus, and the cerebral aqueduct. We also showed that Lgi1-expressing cells co-express nestin, DCX, and beta-III tubulin suggesting that Lgi1-expressing cells are migratory neuroblasts.
These observations imply that Lgi1 may have a role in establishing normal brain architecture and neuronal functions during brain development suggesting that it may be involved in neurogenesis and neuronal plasticity, which become more specifically defined in the adult animal.
The Lgi1 gene  predisposes to the development of a rare form of partial epilepsy with autosomal dominant inheritance and high penetrance , referred to both as Autosomal Dominant Partial Epilepsy with Auditory Features (ADPEAF)  and Autosomal Dominant Temporal Lobe Epilepsy (ADTLE) . It has also been shown recently that Lgi1 is the auto antigen responsible for limbic encephalitis, previously thought to be caused by autoantibodies against voltage gated potassium channels . These patients are part of the group of autoimmune synaptic encephalopathies and exhibit seizures and neuropsychiatric disorders. Lgi1 is a secreted protein [6–8] and has also been implicated in cell movement and invasion in glioma cells  through suppression of the ERK signaling pathway that results in down regulation of matrix metalloproteinases . Recent studies have shown that Lgi1 interacts with a number of different proteins that are related to synaptic function [11–13], notably members of the ADAM family of proteins (ADAM11, ADAM22 and ADAM23), which represent some of the Lgi1 receptors [12–14]. Most recently , Lgi1 was also shown to interact with the Nogo receptor 1 (NgR1) and enhances neuronal growth on myelin based inhibitory substrates and antagonizes myelin-induced growth cone collapse. Mutant null mice for Lgi1 show early onset seizures [16–18], as do mice null for ADAM22 and ADAM23 [19, 20]. Thus, Lgi1 represents the only hereditary epilepsy predisposition gene which is not a channelopathy and offers the opportunity to understand different mechanisms behind seizures in these individuals.
Analysis of mutant null mice has demonstrated that Lgi1 is clearly involved in synapse transmission [16, 17], although, whether it also plays a role in normal brain development is not clear. Although abnormal structures within the brains of ADLTE patients have been reported by several groups [4, 21–23], the level of resolution afforded using current imagining technologies precludes detailed evaluations of these potential abnormalities. Clearly, a better understanding of the cell lineages which express Lgi1 during mammalian brain development will be important in defining its overall function.
Extensive analysis of gene expression in the brain of adult mice demonstrated that the hippocampus and cortex were the predominant regions expressing Lgi1 [24, 25], even though the resolution of the cell lineages involved was relatively low using this approach. Immunohistochemical studies in humans have confirmed these broad observations, although many of the antibodies used in these studies have either been shown to cross react with other members of the Lgi1 family of proteins  or have not been tested for cross reactivity. To overcome this potential limitation, we developed a BAC transgenic mouse in which the GFP reporter gene was placed under the control of Lgi1 cis-regulatory elements . In these BAC transgenics the GFP gene is expressed in cells which have the transcriptional capability of expressing the endogenous Lgi1 gene, and these cells can be identified using conventional immunohistochemistry. This system has been extensively used as part of the GENSAT program to define expression patterns of genes expressed in the central nervous system of adult mice . To date, however, there have been no reported studies of Lgi1 expression patterns at the cellular level during embryonic development. In this report, we describe an immunohistochemical study of the developing brain and associated structures of the nervous system from embryonic days E9.5-E18.5 and postnatal days P1-P20. These studies show that Lgi1 expression is widespread in the developing brain. More interestingly, co-staining studies shown that Lgi1 is expressed in migratory neuroblast cell lineages.
The Lgi1 BAC transgenic system
BAC transgenic technology is now well established  and has been used extensively to define gene expression patterns through the insertion of a GFP reporter into the target gene in the context of its endogenous cis-regulatory elements . Thus, with the caveat that regulatory elements that lie some distance away from the promoter may not be present on the BAC, any cell capable of activating the endogenous promoter of a given gene will also activate the reporter gene carried on the transgenic BAC clone. This system has been developed to overcome many shortcomings of antibodies, whose limitations may include, low specificity for the target protein, cross reactivity with homologous proteins, or poor recognition of the endogenous protein in its native conformation. It should be noted, however, that GFP is only a reporter for endogenous gene expression patterns and does not define the intracellular localization of the protein it reports. As such, the intracellular fluorescence signal reflects the ubiquitous distribution of GFP protein. Typically, multiple tandem BAC integrations occur during construction of the transgenic animals which fortuitously provides a strong GFP signal. In our case, >40 copies of the BAC are present in mice used in this study . This reporter system, therefore, has the added advantage of allowing the visualization of expression patterns for genes which normally show low levels of expression or which, like Lgi1 [6, 8], are normally rapidly secreted and so may be more difficult to visualize using traditional antibodies. Importantly, since the BAC shows multiple tandem integration events , the intensity of the GFP fluorescence does not reflect the intensity of the endogenous gene expression, although relative expression levels between different cells in the same field can be used as a means of determining comparative Lgi1 expression levels.
Lgi1 expression during embryonic development
Lgi1 expression in the early postnatal stages of the murine brain
Within the cerebral cortex at stage P5, moderate expression levels were seen in layers II/III and V of the neocortex. Expression in the hippocampus was maintained unchanged at this stage, with moderate levels seen in the dentate gyrus. We also observed Lgi1 expressing cells in the striatum (caudate/putamen), as shown in figures 8B.1 and 8B.2. Within the thalamus, Lgi1 protein levels were still weak, although the paraventricular thalamic region showed strong expression at this stage (Figure 8C.1). In the midbrain, expression was seen in the pretectal and tectal regions, tegmentum, and both superior and inferior colliculi, which became more diffuse at this stage. Within the pons, cerebellum and medulla oblongata the expression was now either weak or absent. The choroid plexus, however, still shows high levels of Lgi1 expression (Figure 8B.1).
Lgi1 expression in the later postnatal stages of the murine brain
Co-expression of Lgi1 with Nestin, Doublecortin, and Beta-III Tubulin
The underlying mechanism behind the genetic predisposition to epilepsy conferred by mutations in the Lgi1 gene is still poorly understood. Although evidence derived from focused electrophysiological studies implicate abnormalities in synaptic transmission leading to hyperexcitability [16, 17, 29], there have also been suggestions that Lgi1 may also have a fundamental role in brain development , which may contribute to the seizure phenotype. In a BAC transgenic model expressing a truncated Lgi1 protein, for example, mutant Lgi1 led to neuronal restructuring involving inhibition of dendritic pruning and an increase in spine density . Gross anatomical analysis of the brain in Lgi1 mutant null mice [16, 18] however, did not reveal any major structural defects, although subtle changes could not be ruled out at this level of analysis. In humans, although imaging studies have been inconsistent [4, 22–24], there are suggestions of abnormalities and reduced focal brain mass in ADTLE patients. Also, in our zebrafish studies, knockdown of Lgi1 in embryos resulted in increased apoptosis in subregions of the brain, leading to an overall reduction in brain size . With the possibility that Lgi1 may play a role in overall brain development, and neuronal cell positioning in particular, it became important to define the structures in the developing brain that express Lgi1, since these are the cell lineages that are potentially most affected by loss of function. In this study we have broadly defined the temporal and spatial expression pattern in the developing brain and have demonstrated that, unlike the more restricted pattern seen in the early postnatal and adult mouse brain, expression of Lgi1 is widespread and highly orchestrated in a variety of cell types and is not restricted to differentiated neurons.
Evidence from our previous in vitro gene expression studies suggested that Lgi1 may have a role in axon guidance and cell migration . Consistent with this suggestion, high levels of Lgi1 expression were found in regions of the developing brain such as the ganglionic eminence (GE), medulla oblongata (MO), ventricular zone (VZ) and telencephalon where mitotic neuronal precursors are located, and from which they migrate to populate the cortex and other areas. Lgi1 expressing cells in the pretectal area, GE, MO and telencephalon showed coexpression of Lgi1 with DCX (a marker for migrating neurons) and nestin (a marker for early stage neural progenitor cells). Nestin is expressed transiently during development and does not persist through adulthood, except in neuroprogenitor cells of the subventricular zone [33, 34] which still showed Lgi1 expression in E18.5 embryos. Interestingly, the presence of cells co-expressing all three genes in this area suggests that these cells are migrating immature neurons. Also, the presence of oriented GFP-positive fibers in the subpial and parenchyma layers of the medulla oblongata suggest that Lgi1 may be involved in the relocation of immature neurons in the mouse subpial medullary region and may play a role in the migration of medullary precerebellar neurons in the caudal medulla .
Evidence from studies in adult brain [25, 36], suggest that expression of Lgi1 is largely restricted to the hippocampus and cortical neurons. However, in our study we have shown that Lgi1 expression can be detected in the cephalic neuroepithelium at E11.5, which coincides with the first signs of neurogenesis in the mouse . The appearance of Lgi1 expression in the cerebral cortex begins at ~E13.5, and peaks at E18.5. As development progresses, expression levels in the cortex progressively diminish. On the other hand, Lgi1 appears not to be involved in early differentiation and maturation of glial lineage since Lgi1-expressing cells do not coexpress RC2 (radial glial cells) or NG2 (oligodendrocyte precursor marker). Even thought differentiated neurons expressed Lgi1, many of these cells do not express MAP2 at the observed stages. We speculate that once these cells have migrated to their final destinations, Lgi1 expression levels decay.
Lgi1 was also found to be strongly expressed in the basal telencephalic plates that will develop into the basal ganglia associated with motor functions. DCX-expressing cells in the ventral portion of the basal telencephalic plates also express Lgi1, suggesting that these DCX-Lgi1-expressing cells migrate and will populate cortical and subcortical regions. In addition, Marín et al  argue that patterning of the basal telencepahlon is crucial for the growth of cortical axons as well as for guiding cortical projections involved in sensory-motor information. The presence of Lgi1 in migrating neuroblasts is consistent with a function in cortical and medullar axon guidance, as suggested by our gene expression studies in model cell systems . Beta-III tubulin is suggested to be one of the earliest markers to signal neuronal commitment in primitive neuroepithelium, and it is accepted as a neuron-specific protein marker, which is highly expressed in cortex at birth and then its expression levels decrease with increasing postnatal development . During brain development, the maturation of neuroblasts into neurons is accompanied by up-regulation of beta-III tubulin. Coexpression of Lgi1 and beta-III tubulin was detected in the ventricular and subventricular zones, as well as the cortical plate, suggesting a conserved neurogenic program in these cells from embryonic stages to adult life, which further implies that Lgi1 may participate in normal neuronal development.
We also observed Lgi1 expression in many areas of the developing sensory system, for example, the tongue (taste buds), eye, and olfactory bulb. The olfactory system is anatomically connected to the amygdala, lateral septum, hypothalamus and the hippocampus, which are part of the limbic system  and which also express Lgi1. This correlation is consistent with a role for Lgi1 in the development of limbic encephalitis . Within the hippocampus, expression levels are found primarily in the dentate gyrus and scarcely within the CA1-CA3 region of the pyramidal cell layer. There is evidence that Lgi1 also regulates intra-hippocampal circuit formation and the dentate gyrus plays a critical role in seizures, since it appears to have low epileptogenic thresholds . Although thalamic protein levels are weak overall, the paraventricular thalamic area expresses Lgi1. According to Huang et al , the thalamic paraventricular nucleus receives the highest innervation from hypothalamic hypocretin/orexin neurons, generating substantial excitation of the medial prefrontal cortex. Major inputs into the anterior thalamic group are from the hypothalamus, the hippocampus, and the tectum while output from this region is mainly to the cingulate gyrus. In the developing mouse eye, Lgi1 expression was seen in the optic vesicle, optic stalk and optic cup, as well as the neural retina and the retinal pigment epithelium. Lgi1 expression is seen in the retinal ganglion layer, and dominant-negative mutations in transgenic mice lead to abnormal postnatal pruning of retinal axons in the visual relay thalamus . In zebrafish studies, Lgi1 expression was seen in the epithelium surrounding the lumen of the optic vesicle  and interestingly, in early zebrafish embryos, loss of Lgi1 results in abnormal eye development , supporting its critical role in development of this organ.
Several general patterns of Lgi1 distribution were apparent during embryonic brain development. Lgi1 expression appears to spread throughout the dorsal-most brain structures with only weak levels in the ventral regions in early embryo stages within the medulla oblongata showing the strongest expression. This dorsoventral differentiation also appears in the hippocampus, where the dentate gyrus showed more robust expression. Lgi1 expression also appears to follow a superficial to deep, as well as a caudal to cephalic axis. At E10.5, the strongest signal was found in the surface ectoderm, as well as the infundibular recess of the diencephalon and dorsal midbrain in the pretectal neuroepithelium. As development progresses, Lgi1 expression moves interiorly into the neocortex and other more caudal structures, expression in the pretectum and diencephalon areas begins to subside, as shown by weak expression in basal ganglia and thalamic nuclei, although expression in the paraventricular thalamic nucleus remains strong at P5. Overall, the spatial and temporal expression profile for Lgi1 during embryogenesis and postnatal stages is consistent with the idea that it plays an important role in normal brain development, especially neuronal migration and synapse formation.
The generation of the LGI1-EGFP BAC transgenic mice has been reported previously . Mice were housed under standard conditions and treated in accordance with the Guidelines for the Care and Use of Laboratory Animals of Medical College of Georgia.
Mouse brains were isolated and immediately frozen in liquid nitrogen. Using a polytron homogenizer, whole embryos or brains were then homogenized in trizol (Invitrogen) and RNA was isolated as recommended by the manufacturer. Lgi1 was amplified using 5'-GATCCATTCCACGCACCGTTCCTC3' (Forward) and 5'TCTTCTCTACGTGGTCCCATTCCA-3' (Reverse) primer sequences and resolved in 1% agarose gels.
Histology and confocal microscopy
Embryos were removed from pregnant female mice and fixed in a 4% paraformaldehyde solution in PBS for at least 24 hours. Embryos were then first dehydrated in stepped concentrations of ethanol solution from 70% to 100% and then placed in xylene before being embedded in paraffin. Brains from neonates were dissected and quickly fixed in 4% paraformaldehyde solution and similarly mounted in paraffin. 7 μm coronal and sagittal sections were collected onto plus-charged glass slides (Fisher Scientific, Pittsburgh, PA). After deparaffinization in xylene, and rehydration, the tissues were permeabilized with 0.1% triton X-100 in PBS. Processed sections were then reacted with specific primary and secondary antibodies (see below). Brightfield and confocal images were obtained using a Zeiss microscope and LSM500 software. Several different reference resources were used as an aid in identification of anatomical structures [44–48].
Immunogen affinity-purified polyclonal anti-EGFP antibody (Abcam, ab6556) was used for confocal analysis. Anti-NG2, anti-Slug, and Doublecortin (sc-18) antibodies were obtained from Santa Cruz Biotechnology, Inc. Anti-Nestin (MAB353) and Anti-Beta III Tubulin (MAB5564) monoclonal antibodies were obtained from Millipore Corporation. Anti-MAP2 was from Cell Signaling, and Anti-RC2 was from UC Davis. The secondary antibodies used for primary antibody detection were peroxidase conjugated anti-rabbit, anti-goat, and anti-mouse IgG, all obtained from Jackson ImmunoResearch Laboratories.
We are grateful to Dr Richard Cameron and Dr. Nahid Mivechi for critical reading of the manuscript and the MCG histology core facility for preparing the tissue sections. This work was supported in part by grant NS046706 from the National Institutes of Health.
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