Kif26b, a kinesin family gene, regulates adhesion of the embryonic kidney mesenchyme.

The kidney develops through reciprocal interactions between two precursor tissues: the metanephric mesenchyme and the ureteric bud. We previously demonstrated that the zinc finger protein Sall1 is essential for ureteric bud attraction toward the mesenchyme. Here, we show that Kif26b, a kinesin family gene, is a downstream target of Sall1 and that disruption of this gene causes kidney agenesis because of impaired ureteric bud attraction. In the Kif26b-null metanephros, compact adhesion between mesenchymal cells adjacent to the ureteric buds and the polarized distribution of integrin alpha8 were impaired, resulting in failed maintenance of Gdnf, a critical ureteric bud attractant. Overexpression of Kif26b in vitro caused increased cell adhesion through interactions with nonmuscle myosin. Thus, Kif26b is essential for kidney development because it regulates the adhesion of mesenchymal cells in contact with ureteric buds.

Notch2 activation in the embryonic kidney depletes nephron progenitors.

Successive activation of Wnt4 and Notch2 generates nephrons from the metanephric mesenchyme. Mesenchymal-to-epithelial transition requires Wnt4, and normal development of the proximal nephron (epithelia of glomeruli and proximal tubules) requires Notch2. It is unknown, however, whether Notch2 dictates the fate of the proximal nephron directly. Here, we generated a mutant strain of mice with activated Notch2 in Six2-containing nephron progenitor cells of the metanephric mesenchyme. Notch2 activation did not skew the cell fate toward the proximal nephron but resulted in severe kidney dysgenesis and depletion of Six2-positive progenitors. We observed ectopic expression of Wnt4 and premature tubule formation, similar to the phenotype of Six2-deficient mice. Activation of Notch2 in the progenitor cells suppressed Pax2, an upstream regulator of Six2, possibly through Hesr genes. Taken together, these data suggest that a positive feedback loop exists between Notch2 and Wnt4, and that Notch2 stabilizes, rather than dictates, nephron fate by shutting down the maintenance of undifferentiated progenitor cells, thereby depleting this population.

Overexpression of Sall1 in vivo leads to reduced body weight without affecting kidney development.

Human SALL1 is a homologue of the Drosophila region-specific homeotic gene sal, and is also known as a causative gene for Townes-Brocks syndrome, which is characterized by multi-organ malformations. We previously demonstrated that mouse Sall1 plays a crucial role in ureteric bud invasion during kidney development, and possibly in nephron progenitor cells in the metanephric mesenchyme. To gain insights into the Sall1 functions in the kidney and other tissues, we generated R26Sall1 mice, in which Rosa26 locus stop sequences flanked by two loxP sites were located upstream of the Sall1 cDNA. This allele allowed exogenous Sall1 expression in a Cre recombinase-dependent manner. R26Sall1 mice were first crossed with CAGCre mice, which expressed Cre recombinase ubiquitously during embryogenesis. Mice expressing Sall1 ubiquitously were smaller in size compared with mice of other genotypes. We then crossed R26Sall1 mice with Six2Cre mice expressing Cre recombinase in the metanephric mesenchyme during kidney development. However, no kidney defects were observed. Taken together, overexpression of Sall1 does not affect kidney development, but does lead to a reduced body weight, suggesting that the optimal dosage of Sall1 is required for normal mouse development.

To be or not to be a flatworm: the acoel controversy.

Since first described, acoels were considered members of the flatworms (Platyhelminthes). However, no clear synapomorphies among the three large flatworm taxa -- the Catenulida, the Acoelomorpha and the Rhabditophora -- have been characterized to date. Molecular phylogenies, on the other hand, commonly positioned acoels separate from other flatworms. Accordingly, our own multi-locus phylogenetic analysis using 43 genes and 23 animal species places the acoel flatworm Isodiametra pulchra at the base of all Bilateria, distant from other flatworms. By contrast, novel data on the distribution and proliferation of stem cells and the specific mode of epidermal replacement constitute a strong synapomorphy for the Acoela plus the major group of flatworms, the Rhabditophora. The expression of a piwi-like gene not only in gonadal, but also in adult somatic stem cells is another unique feature among bilaterians. These two independent stem-cell-related characters put the Acoela into the Platyhelminthes-Lophotrochozoa clade and account for the most parsimonious evolutionary explanation of epidermal cell renewal in the Bilateria. Most available multigene analyses produce conflicting results regarding the position of the acoels in the tree of life. Given these phylogenomic conflicts and the contradiction of developmental and morphological data with phylogenomic results, the monophyly of the phylum Platyhelminthes and the position of the Acoela remain unresolved. By these data, both the inclusion of Acoela within Platyhelminthes, and their separation from flatworms as basal bilaterians are well-supported alternatives.

Switching language switches mind: linguistic effects on developmental neural bases of 'Theory of Mind'.

Theory of mind (ToM)--our ability to predict behaviors of others in terms of their underlying intentions--has been examined through false-belief (FB) tasks. We studied 12 Japanese early bilingual children (8-12 years of age) and 16 late bilingual adults (18-40 years of age) with FB tasks in Japanese [first language (L1)] and English [second language (L2)], using fMRI. Children recruited more brain regions than adults for processing ToM tasks in both languages. Moreover, children showed an overlap in brain activity between the L1 and L2 ToM conditions in the medial prefrontal cortex (mPFC). Adults did not show such a convergent activity in the mPFC region, but instead, showed brain activity that varied depending on the language used in the ToM task. The developmental shift from more to less ToM specific brain activity may reflect increasing automatization of ToM processing as people age. These results also suggest that bilinguals recruit different resources to understand ToM depending on the language used in the task, and this difference is greater later in life.

Trb2, a mouse homolog of tribbles, is dispensable for kidney and mouse development.

Glomeruli comprise an important filtering apparatus in the kidney and are derived from the metanephric mesenchyme. A nuclear protein, Sall1, is expressed in this mesenchyme, and we previously reported that Trb2, a mouse homolog of Drosophila tribbles, is expressed in the mesenchyme-derived tissues of the kidney by microarray analyses using Sall1-GFP knock-in mice. In the present report, we detected Trb2 expression in a variety of organs during gestation, including the kidneys, mesonephros, testes, heart, eyes, thymus, blood vessels, muscle, bones, tongue, spinal cord, and ganglions. In the developing kidney, Trb2 signals were detected in podocytes and the prospective mesangium of the glomeruli, as well as in ureteric bud tips. However, Trb2 mutant mice did not display any apparent phenotypes and no proteinuria was observed, indicating normal glomerular functions. These results suggest that Trb2 plays minimal roles during kidney and mouse development.

Cultural and linguistic effects on neural bases of 'Theory of Mind' in American and Japanese children.

Theory of Mind (ToM) has been defined as our ability to predict behaviors of others in terms of their underlying intentions. While the developmental trajectory of ToM had been thought to be invariant across cultures, several ToM studies conducted outside the Anglo-American cultural or linguistic milieus have obtained mixed results. To examine effects of culture/language on the development of neural bases of ToM, we studied 12 American monolingual children and 12 Japanese bilingual children with second-order false-belief story and cartoon tasks, using functional magnetic resonance imaging (fMRI). While a few brain regions such as ventro-medial prefrontal cortex (vmPFC) and precuneus were recruited by both cultural/linguistic groups, several brain areas including inferior frontal gyrus (IFG) and temporo-parietal junction (TPJ) were employed in a culture/language-dependent manner during the ToM tasks. These results suggest that the neural correlates of ToM may begin to vary depending upon cultural/linguistic background from early in life.

Wnt signaling is required for antero-posterior patterning of the planarian brain.

Wnt signaling functions in axis formation and morphogenesis in various animals and organs. Here we report that Wnt signaling is required for proper brain patterning during planarian brain regeneration. We showed here that one of the Wnt homologues in the planarian Dugesia japonica, DjwntA, was expressed in the posterior region of the brain. When DjwntA-knockdown planarians were produced by RNAi, they could regenerate their heads at the anterior ends of the fragments, but formed ectopic eyes with irregular posterior lateral branches and brain expansion. This suggests that the Wnt signal may be involved in antero-posterior (A-P) patterning of the planarian brain, as in vertebrates. We also investigated the relationship between the DjwntA and nou-darake/FGFR signal systems, as knockdown planarians of these genes showed similar phenotypes. Double-knockdown planarians of these genes did not show any synergistic effects, suggesting that the two signal systems function independently in the process of brain regeneration, which accords with the fact that nou-darake was expressed earlier than DjwntA during brain regeneration. These observations suggest that the nou-darake/FGFR signal may be involved in brain rudiment formation during the early stage of head regeneration, and subsequently the DjwntA signal may function in A-P patterning of the brain rudiment.

Children's and adults' neural bases of verbal and nonverbal 'theory of mind'.

Theory of mind (ToM) - our ability to predict behaviors of others in terms of their underlying intentions - has been examined through verbal and nonverbal false-belief (FB) tasks. Previous brain imaging studies of ToM in adults have implicated medial prefrontal cortex (mPFC) and temporo-parietal junction (TPJ) for adults' ToM ability. To examine age and modality related differences and similarities in neural correlates of ToM, we tested 16 adults (18-40 years old) and 12 children (8-12 years old) with verbal (story) and nonverbal (cartoon) FB tasks, using functional magnetic resonance imaging (fMRI). Both age groups showed significant activity in the TPJ bilaterally and right inferior parietal lobule (IPL) in a modality-independent manner, indicating that these areas are important for ToM during both adulthood and childhood, regardless of modality. We also found significant age-related differences in the ToM condition-specific activity for the story and cartoon tasks in the left inferior frontal gyrus (IFG) and left TPJ. These results suggest that depending on the modality adults may utilize different brain regions from children in understanding ToM.

The murine homolog of SALL4, a causative gene in Okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with Sall1 in anorectal, heart, brain and kidney development.

Mutations in SALL4, the human homolog of the Drosophila homeotic gene spalt (sal), cause the autosomal dominant disorder known as Okihiro syndrome. In this study, we show that a targeted null mutation in the mouse Sall4 gene leads to lethality during peri-implantation. Growth of the inner cell mass from the knockout blastocysts was reduced, and Sall4-null embryonic stem (ES) cells proliferated poorly with no aberrant differentiation. Furthermore, we demonstrated that anorectal and heart anomalies in Okihiro syndrome are caused by Sall4 haploinsufficiency and that Sall4/Sall1 heterozygotes exhibited an increased incidence of anorectal and heart anomalies, exencephaly and kidney agenesis. Sall4 and Sall1 formed heterodimers, and a truncated Sall1 caused mislocalization of Sall4 in the heterochromatin; thus, some symptoms of Townes-Brocks syndrome caused by SALL1 truncations could result from SALL4 inhibition.