We report three patients with selective topographic disorientation due to small, focal hemorrhages extending from the right retrosplenial region to the medial parietal lobe. All three could discriminate and identify familiar buildings and landscapes, but had great difficulty remembering spatial positional relationships between two distant locations (i.e., the direction from one location to another) in familiar areas. These symptoms were different than the perception and memory deficits for buildings and landscapes caused by the medial temporo-occipital lesion. These findings suggest that the directional orientation between two locations within a familiar area ("sense of direction") is closely associated with the right retrosplenial region and the medial parietal lobe in humans.

Dynamic changes in neuronal morphology and transcriptional regulation play crucial roles in the neuronal network and function. Accumulating evidence suggests that the megakaryoblastic leukemia (MKL) family members, which function not only as actin-binding proteins but also as serum response factor (SRF) transcriptional coactivators, regulate neuronal morphology. However, the extracellular ligands and signaling pathways, which activate MKL-mediated morphological changes in neurons, remain unresolved. Here, we demonstrate that in addition to MKL1, MKL2, highly enriched in the forebrain, strongly contributes to the dendritic complexity, and this process is triggered by stimulation with activin, a member of the transforming growth factor ␤ (TGF-␤) superfamily. Activin promoted dendritic complexity in a SRF-and MKL-dependent manner without drastically affecting MKL localization and protein levels. In contrast, activin promoted the nuclear export of suppressor of cancer cell invasion (SCAI), which is a corepressor for SRF and MKL. Furthermore, overexpression of SCAI blocked activin-induced SRF transcriptional responses and dendritic complexity. Collectively, these results strongly suggest that activin-SCAI-MKL signaling is a novel pathway that regulates the dendritic morphology of rat cortical neurons by excluding SCAI from the nucleus and activating MKL/SRF-mediated gene expression. Serum response factor (SRF)4 is a transcription factor that binds to a consensus sequence CC(A/T) 6 GG (called the CArG box), which is present in the promoters of several immediateearly or cytoskeletal genes (1). Several studies have demonstrated that deletion mutants of SRF in the mouse brain result in the attenuation of activity-dependent expression of immediate-early genes, impair synaptic plasticity and learning (2, 3), reduce neurite outgrowth, and show abnormality of pathfindings and neuronal migration (4, 5). These findings strongly suggest that SRF plays an important role in neuronal development and plasticity (6). SRF-dependent transcription is controlled by at least two different types of coactivators. One comprises the ternary complex factors, which mainly regulate the immediateearly genes such as c-fos (7). The other type of coactivator comprises megakaryoblastic leukemia (MKL) family members. The MKL family consists of megakaryocytic acute leukemia/ megakaryoblastic leukemia 1/myocardin-related transcription factor-A/basic SAP, and coiled-coil domain (MAL/MKL1/ MRTF-A/BSAC) and MKL2/MRTF-B (8 -13). In nonneuronal cells, MKL1 is primarily activated by actin rearrangement stimulated with the activation of Rho GTPases; that is, release of MKL1 from G-actin enables MKL1 to translocate to the nucleus where it binds to and activates SRF (14). MKL2, in addition to MKL1, regulates a set of cytoskeletal genes (11, 12). Furthermore, suppressor of cancer cell invasion (SCAI) has recently been identified as an MKL-interacting cofactor that inhibits cancer cell invasion (15). Therefore, SRF-driven transcriptional regulation appears to be ...

A 62-year-old right-handed man gradually experienced increasing difficulty with speech and manual dexterity. He had apraxia of speech, buccofacial apraxia, and complex limb apraxia as well as terminal dementia. At autopsy, focal cortical atrophy, neuronal loss, and neuropil rarefaction in the second and third cortical layers were most prominent in the left opercular, lower precentral, superior parietal, and left temporal pole. Numerous Pick bodies were diffusely present in the temporal and posterior frontal lobes and, to a lesser degree, in the superior parietal lobule. This report demonstrates an association between the distribution of Pick's pathology and several apraxic impairments.

Although it is well established that RhoA signaling pathways play key roles in regulating neuronal morphology, their involvement in other aspects of neuronal function has received little attention. Recent studies have elucidated a novel intracellular signaling pathway used by RhoA to elicit activation of serum response factor (SRF)-mediated transcription. In this pathway, activation of RhoA triggers nuclear translocation of the SRF co-activator, megakaryocytic acute leukemia (MAL). In assessing whether RhoA regulates transcription in neurons via this pathway, we have found that a constitutively active form of Tech (transcript-enriched in cortex and hippocampus), a RhoA guanine nucleotide exchange factor (GEF) that is expressed in forebrain neurons, stimulates SRF reporter activity in extracts of primary cortical cultures and induces nuclear translocation of MAL in cortical neurons. Both of these responses appear to be mediated by Tech's activation of RhoA as they are not mimicked by a mutant Tech construct lacking RhoA GEF activity and are blocked by C3 transferase, a selective inhibitor of RhoA. Furthermore, Techinduced increases in SRF activity are suppressed by a dominant negative MAL construct. These findings demonstrate that RhoA signaling pathways are able to regulate transcription in neurons by triggering translocation of the SRF co-activator MAL.

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