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The Development of the Mammalian Central Chapter 5: GRIPE is a novel gene that may assume different roles during development and in adulthood Chapter 5: GRIPE is a novel gene that may assume different roles during development and in adulthood 5.1. Characterisation of GRIPE and E12 mRNA expression during development As a first step towards describing the expression of GRIPE and E12 during neurodevelopment, Northern analysis was conducted to acquire a global pattern of mRNA expression. To do this, embryonic and adult tissues were harvested for RNA isolation as described (Section 2.2). Northern hybridisation was then performed using radiolabelled GRIPE and E12 cDNAs as probes, and these results are shown in Fig. 5.1. A single band of approximately 8kb is detected in all samples; this was the only signal detected in all northern hybridisations performed with different GRIPE cDNA and cRNA probes (see Appendix 10.2). It would appear that GRIPE mRNA is abundant in the head and trunk at e11.5, and levels decrease during embryogenesis, and are undetectable by e17.5. In the adult, GRIPE is abundant in the brain, but is undetectable in the placenta and kidney. However, further RT-PCR experiments (see Figs 6.8 and 6.13) indicate that GRIPE is weakly detectable in these tissues, but not in the kidney. Northern analysis of E12 mRNA shows high levels of expression at e11.5, with a gradual decrease during embryogenesis, and is almost undetectable by e17.5. Further, E12 is undetectable in adult brain, placenta and kidney. These observations demonstrate a coincidence in expression of GRIPE and E12 mRNA during embryogenesis, but not in the adult; where E12 mRNA is undetectable. In consideration of their protein- protein interaction described in the previous chapter, these observations bring up the possibility that the interaction between GRIPE and E12 may be important during neurogenesis, but not in the adult central nervous system. 5.2. GRIPE is an approximately 8kb polyadenylated mRNA The size of the mature GRIPE transcript was further investigated by Northern analysis, performed with isolated polyadenylated mRNA. Messenger RNA was isolated using a standard oligo-d(T) cellulose method and Northern hybridisation performed as described (section 2.14). As shown in Fig. 5.2, the only detectable GRIPE mRNA signal is approximately 8 kb in size. In a pattern consistent with Northern analysis of total RNA (Fig. 5.1), the signal is high in e11.5 head and trunk (lanes 1 and 2 respectively), as well as in adult brain (lane 5), but is weakly detectable in e17.5 tissues (lanes 3 and 4). Further, the hybridised signal in total RNA derived from e11.5 trunk (lane 6) is identical to that detected in oligo-d(T) 65 e11.5 e12.5 e13.5 e14.5 e15.5 e17.5 h t h t h t h t h t h t ab pl k GRIPE E12 18S rRNA Figure 5.1. Characterisation of GRIPE and E12 mRNA expression. Northern blot of GRIPE transcript in total RNA isolated from mouse embryonic head (h) or trunk (t) at different stages of embryogenesis. Levels of GRIPE decrease during development, but remain high in adult brain (ab), and is low in placental (pl) and adult kidney (k) RNA. GRIPE expression correlates with the expression of E12 mRNA during embryogenesis. 1 2 3 4 5 6 28S 18S 5S GAPDH Figure 5.2. GRIPE is expressed as an approximately 8kb polyadenylated mRNA. Messenger RNA was isolated from 500µg of total RNA and electrophoresed on an agarose-formaldehyde gel before Northern blotting. GRIPE mRNA signal (arrow) is enriched after mRNA selection (lane 2), with respect to the same signal in total RNA from the same source of tissue (lane 6). Signals for GAPDH confirmed enrichment for mRNA after oligo-d(T) selection (compare lanes 2 and 6). Lane 1: 5µg e11.5 head poly A+ mRNA, Lane 2: 5µg e11.5 trunk poly A+ mRNA, Lane 3: 5µg e17.5 head poly A+ mRNA, Lane 4: 5µg e17.5 trunk poly A+ mRNA, Lane 5: 5µg adult brain poly A+ mRNA, Lane 6: 15µg total RNA from e11.5 trunk. 65i Chapter 5: GRIPE is a novel gene that may assume different roles during development and in adulthood purified mRNA preparations (compare lanes 2 and 6). Taken together, these data indicate that the mature GRIPE transcript is a polyadenylated 8kb mRNA, and is the only signal detected by Northern analysis. 5.3. The interaction of GRIPE and E12 may be important for early neurogenetic events, but not in the adult brain. To identify sites of GRIPE and E12 mRNA expression, in situ hybridisations were performed on 10µm sections of embryonic mouse tissue and adult brain (described in section 2.16). At e11.5, GRIPE and E12 are coincidentally detected in the ventricular zone of the developing forebrain, as well as in the mandibular arch (Figs. 5.3A,B; short and long arrows respectively). Parallel experiments conducted with corresponding sense control probes confirmed the detection of specific signals (Figs. 5.3C and D for GRIPE and E12 respectively). In addition, tissue sections incubated without probe during hybridisation ruled out non-specific binding of DIG antibody and alkaline phosphatase activity (data not shown). In situ hybridisation experiments carried out with sections of e13.5 and e15.5 embryos were not successful. In adult brain, GRIPE displays a widespread expression pattern, with prominent staining in the CA formation and dentate gyrus of the hippocampus (Fig. 5.4A, short arrow), as well as in deep layer neurons of the cerebral cortex (Fig. 5.4A, arrowhead), and in the frontal cortex (Fig. 5.4C, arrow). No specific staining was detected in the adult cerebellum (not shown). Experiments performed with coronal sections of adult mouse brain reveal staining in neurons of the medial habenula nuclei (Fig. 5.5A, arrowhead), piriform cortex and posterior basomedial amygdala (arrow and arrowhead in Fig.5.5B, respectively). In contrast to GRIPE expression, E12 mRNA is undetectable in adult brain (Fig. 5.4B, arrowhead and arrow); an observation which is consistent with the results from Northern analysis. Taken together, these results suggest that the interaction of GRIPE and E12 may be functionally more significant during the neurogenetic period rather than in the adult. In particular, ventricular zone cells in the developing forebrain may require an intact GRIPE/E12 signalling pathway for proper migration and differentiation. 66 A B C D GRIPE E12 Figure 5.3. Localisation of GRIPE and E12 RNA. (A) In situ hybridisation reveals that GRIPE is expressed in most tissues of the e11.5 mouse embryo, including the ventricular zone of the neuroepithelium (short arrow) and mandibular arch (long arrow), but is absent in the heart (arrowhead). Similarly, E12 RNA is found in similar tissues (B). Panels C and D are sense probe controls for GRIPE and E12, showing the absence of specific staining. Scale bar represents 100 µm. 66i A GRIPE B E12 B C D C GRIPE Figure 5.4. Localisation of GRIPE RNA in adult mouse brain. In situ hybridisation on sagittal sections of adult mouse brain show that GRIPE is expressed in the CA formation of the hippocampus (panel A, short arrow). In addition, staining is detected in deep layer neurons of the cerebral cortex (arrowhead in B), as well as in neurons of the frontal cortex (arrow in panel C). Conversely, in situ hybiridsation with an E12 probe reveals lack of expression in adult brain. Parasagittal section of rodent brain on Panel D as a guide for location of brain slices in A-C (from Swanson, 1992) A A GRIPE B Figure 5.5. In situ hybridisation of coronal sections of adult brain. Coronal sections of adult brain indicate that GRIPE is expressed in neurons of the cerebral cortex, hippocampus and medial habenula nuclei (panel A, long arrow, short arrow and arrow head respectively).Furthermore, neurons of the priform cortex and posterior basomedial amygdala also express GRIPE (panel B, arrow and arrowhead respectively). Panel C depicts a coronal section of rodent brain for orientationof tissue slices in A and B (from Swanson, 1992). B GRIPE 66ii Chapter 5: GRIPE is a novel gene that may assume different roles during development and in adulthood 5.4. GRIPE mRNA is upregulated in differentiating neurons. To further investigate the association of GRIPE/E12 expression with neurogenesis, an in vitro approach was adopted. The mouse embryocarcinoma cell line P19 was induced to differentiate into neurons using retinoic acid, thereby producing an enriched population of neurons in culture (see Section 2.17). As shown in Fig. 5.6, bright field photomicrographs show undifferentiated cells (arrows in panel A) which are induced to aggregate in the presence of retinoic acid (panel B). These aggregates are finally plated, and clusters of differentiated cells have extended projections by Day 8 (panel C). Next, immunocytochemistry was performed with neuronal and glial specific markers to deduce the numbers of neurons and glia after 8 days in culture. As shown, neuronal nuclei are positive for NeuN (arrows in panel D), a known marker of neurogenesis (Mullen et al., 1992). Immunostaining for GFAP identified glial cells in the same field (arrow in panel E; panel F). On the other hand, undifferentiated P19 cells, which do not exhibit a neuronal or glial phenotype (McBurney and Rogers, 1982), do not stain for NeuN (panel H) or GFAP(data not shown). Quantitation of the numbers of NeuN+ and GFAP+ cells revealed that greater than 98% of cells in culture were neurons by Day 8 (data not shown). Following from these analyses, protein extracts were harvested and Western blot analysis performed to chart the progress of neurodifferentiation using established molecular markers.
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