SummaryThe development of the mammalian brain is dependent on extensive neuronal migration. Mutations in mice and humans that affect neuronal migration result in abnormal lamination of brain structures with associated behavioral deficits. Here, we report the identification of a hyperactive N-ethyl-N-nitrosourea (ENU)-induced mouse mutant with abnormalities in the laminar architecture of the hippocampus and cortex, accompanied by impaired neuronal migration. We show that the causative mutation lies in the guanosine triphosphate (GTP) binding pocket of α-1 tubulin (Tuba1) and affects tubulin heterodimer formation. Phenotypic similarity with existing mouse models of lissencephaly led us to screen a cohort of patients with developmental brain anomalies. We identified two patients with de novo mutations in TUBA3, the human homolog of Tuba1. This study demonstrates the utility of ENU mutagenesis in the mouse as a means to discover the basis of human neurodevelopmental disorders.

Cortical afferents to area V1 were studied in seven Cebus monkeys by means of retrograde fluorescent tracers. Injections were placed in V1, under electrophysiological guidance, in the regions of representation of both the upper and lower visual quadrants, at eccentricities that ranged from 0.5 to 64 degrees. In all cases retrogradely filled neurons were found in retinotopically corresponding portions of areas V2 and MT, as defined electrophysiologically (Rosa et al: J. Comp. Neurol. 275:326, 1988; Fiorani et al: J Comp Neurol 287:98, 1989). The results also revealed two other visual zones located anterior to V2 here named third and fourth visual areas. A topographical organization of the connections was observed in these areas, with upper quadrant located ventrally and lower quadrant located dorsally. A clear central-peripheral gradient, from the lateral to the medial cortical surface, was also observed in these areas. Lower field injections revealed crude topographic organization in area DZ and a diffuse projecting zone in the annectent gyrus. Peripheral injections in V1 revealed a clear upper and lower field segregation in areas PO and prostriata as well as a complex topography in MST. In addition, another region of labeling revealed the presence of an area, the temporal ventral posterior region, with an organized topographic representation of the upper field, with a central to peripheral gradient, from the lateral to the medial cortical surface. Three groups of cortical areas were distinguished according to the laminar distribution of neurons labeled from V1. In the first group, which is characterized by dense infra- and supragranular labeling, only V2 was included. The second group consists of areas V3, MT, and PO. These areas show dense labeling in the infragranular layers and occasionally sparse labeling in the supragranular layers. Finally, V4 and the other projecting areas, which are characterized by exclusive labeling of the infragranular layers were included in the third group.

The transcription factor Pax6 has been implicated in neocortical neurogenesis in vertebrates, including humans. Analyses of the role of Pax6 in layer formation and cognitive abilities have been hampered by perinatal lethality of Pax6 mutants. Here, we generated viable mutants exhibiting timed, restricted inactivation of Pax6 during early and late cortical neurogenesis using Emx1-Cre and hGFAP-Cre lines, respectively. The disruption of Pax6 at the onset of neurogenesis using Emx1-Cre line resulted in premature cell cycle exit of early progenitors, increase of early born neuronal subsets located in the marginal zone and lower layers, and a nearly complete absence of upper layer neurons, especially in the rostral cortex. Furthermore, progenitors, which accumulated in the enlarged germinal neuroepithelium at the pallial/subpallial border in the Pax6 mutants, produced an excess of oligodendrocytes. The inactivation of Pax6 after generation of the lower neuronal layers using hGFAP-Cre line did not affect specification or numbers of late-born neurons, indicating that the severe reduction of upper layer neurons in Pax6 deficiency is mostly attributable to a depletion of the progenitor pool, available for late neurogenesis. We further show that Pax6 fl/fl ;Emx1-Cre mutants exhibited deficiencies in sensorimotor information integration, and both hippocampus-dependent short-term and neocortex-dependent long-term memory recall. Because a majority of the morphological and behavior disabilities of the Pax6 mutant mice parallel abnormalities reported for aniridia patients, a condition caused by PAX6 haploinsufficiency, the Pax6 conditional mutant mice generated here represent a valuable genetic tool to understand how the developmental cortical disruption can lead to a human behavior abnormality.

We tested current hypotheses on the functional organization of the third visual complex, a particularly controversial region of the primate extrastriate cortex. In anatomical experiments, injections of retrograde tracers were placed in the dorsal cortex immediately rostral to the second visual area (V2) of New World monkeys (Callithrix jacchus), revealing the topography of interconnections between the "third tier" cortex and the primary visual area (V1). The data indicate the presence of a dorsomedial area (DM), which represents the entire upper and lower quadrants of the visual field, and which receives strong, topographically organized projections from the superficial layers of V1. The visuotopic organization and boundaries of DM were confirmed by electrophysiological recordings in the same animals and by architectural characteristics which were distinct from those found in ventral extrastriate cortex rostral to V2. There was no electrophysiological or histological evidence for a transitional area between V2 and DM. In particular, the central representation of the upper quadrant in DM was directly adjacent to the representation of the horizontal meridian that marks the rostral border of V2. The present results argue in favor of the hypothesis that the third visual complex in New World monkeys contains different areas in its dorsal and ventral components: area DM, near the dorsal midline, and a homolog of area 19 of other mammals, located more lateral and ventrally. The characteristics of DM suggest that it may correspond to visual area 6 (V6) of Old World monkeys.

Two visual areas of the anterior bank of the parietooccipital sulcus, areas PO and POd, were identified and their visual field representations were studied in six anesthetized and paralyzed Cebus monkeys. The definition of these areas was based on electrophysiological mapping and myeloarchitecture. PO is located in the ventral aspect of the anterior bank of the parietooccipital sulcus and ventral precuneate gyrus. It borders area V2 posteriorly and ventrally in the depth of the parietooccipital sulcus, area V3d laterally, and another undescribed visual area medially. POd was located dorsal to area PO and ventral to architectonic area PE. The representations of the visual field in areas PO and POd are complex. In each hemisphere, these areas have a virtually complete representation of the contralateral visual hemifield. Different from the previously described visual areas, in PO and POd there is a precise organization of isopolar lines and a complex organization of the isoeccentric ones. In PO, as well as in POd, the representation of the horizontal meridian runs dorsoventrally along the parietooccipital sulcus. The upper visual quadrant is represented medially and the lower visual quadrant laterally. A large and complex representation of the periphery, from 20 degrees to 60 degrees eccentricity is present at the lateral and medial portions of these areas. By contrast, the representation of the central 20 degrees is very small in both PO and POd. The central visual field is represented ventrally in PO and dorsally in area POd. Area POd shows a more stratified myeloarchitectonic pattern than PO and both areas can be distinguished from other surrounding areas by their heavier myelinated pattern.