Integrin Signaling in the Central Nervous System in Animals and Human Brain Diseases.

The integrin family is involved in various biological functions, including cell proliferation, differentiation and migration, and also in the pathogenesis of disease. Integrins are multifunctional receptors that exist as heterodimers composed of α and ß subunits and bind to various ligands, including extracellular matrix (ECM) proteins; they are found in many animals, not only vertebrates (e.g., mouse, rat, and teleost fish), but also invertebrates (e.g., planarian flatworm, fruit fly, nematodes, and cephalopods), which are used for research on genetics and social behaviors or as models for human diseases. In the present paper, we describe the results of a phylogenetic tree analysis of the integrin family among these species. We summarize integrin signaling in teleost fish, which serves as an excellent model for the study of regenerative systems and possesses the ability for replacing missing tissues, especially in the central nervous system, which has not been demonstrated in mammals. In addition, functions of astrocytes and reactive astrocytes, which contain neuroprotective subpopulations that act in concert with the ECM proteins tenascin C and osteopontin via integrin are also reviewed. Drug development research using integrin as a therapeutic target could result in breakthroughs for the treatment of neurodegenerative diseases and brain injury in mammals.

From the olfactory bulb to higher brain centers: genetic visualization of secondary olfactory pathways in zebrafish.

In the vertebrate olfactory system, odor information is represented as a topographic map in the olfactory bulb (OB). However, it remains unknown how this odor map is transferred from the OB to higher olfactory centers. Using genetic labeling techniques in zebrafish, we found that the OB output neurons, mitral cells (MCs), are heterogeneous with respect to transgene expression profiles and spatial distributions. Tracing MC axons at single-cell resolution revealed that (1) individual MCs send axons to multiple target regions in the forebrain; (2) MCs innervating the same glomerulus do not necessarily display the same axon trajectory; (3) MCs innervating distinct glomerular clusters tend to project axons to different, but partly overlapping, target regions; (4) MCs innervating the medial glomerular cluster directly and asymmetrically send axons to the right habenula. We propose that the topographic odor map in the OB is not maintained intact, but reorganized in higher olfactory centers. Moreover, our finding of asymmetric bulbo-habenular projection renders the olfactory system an attractive model for the studies of brain asymmetry and lateralized behaviors.

Pharmacological effects on mirror approaching behavior and neurochemical aspects of the telencephalon in the fish, medaka (Oryzias latipes).

Shoaling can be considered a simple form of affective behavior displayed by social fish in which a single fish exhibits an tendency to approach others. In the present study, we adopted a dual approach to investigate shoaling behavior in the medaka fish (Oryzias latipes): a behavioral pharmacological approach to assess mirror approaching behavior and an immunohistochemical approach to examine the neurotransmitter distribution in the medaka telencephalon. In order to gain an insight into shoaling activity, we examined the pharmacological effects of the positive allosteric modulator of the gamma-aminobutyric acid (GABA) anti-anxiety drug, diazepam, and chlorpromazine, a predominantly dopaminergic antagonist on mirror approaching behavior and, in particular, mirror approaching time (MAT; a tendency to shoal) and swimming distance (SWD). Diazepam dose-dependently suppressed MAT, but had no effect on SWD. Conversely, chlorpromazine suppressed SWD without having effects on MAT. The present study demonstrates for the first time that an anti-anxiety drug selectively modifies shoaling behavior in fish. Although the mechanism of this modification remains to be fully identified, immunohistochemical analysis suggests that a positive allosteric modulator of GABA acts on two distinct telencephalic regions. Mirror approaching behavior therefore revealed a close relationship with the action of the GABA-nergic system and not the dopaminergic system in the medaka telencephalon.

Lhx2 mediates the activity of Six3 in zebrafish forebrain growth.

The telencephalon shows the greatest degree of size variation in the vertebrate brain. Understanding the genetic cascade that regulates telencephalon growth is crucial to our understanding of how evolution of the normal human brain has supported such a variation in size. Here, we present a simple and quick approach to analyze this cascade that combines caged-mRNA technology and the use of antisense morpholino oligonucleotides in zebrafish embryos. Lhx2, a LIM-homeodomain protein, and Six3s (Six3b and Six3a), another homeodomain proteins, show very similar expression patterns early in forebrain development, and these are known to be involved in the growth of this part of the brain. The telencephalon of six3b and six3a double morphant (six3 morphant) embryos is markedly reduced in size due to impaired cellular proliferation. Head-specific overexpression of Lhx2 by photoactivation of a caged-lhx2 mRNA completely rescued this size reduction, whereas similar head-specific activation of Six3b could not rescue the knockdown effect of lhx2. In the forebrain of medaka embryos, Six3 facilitates cellular proliferation by sequestration of Geminin from Cdt1, a key component in the assembly of the prereplication complex. Our results suggest that Lhx2 may mediate an alternative or parallel pathway for control of cellular proliferation in the developing forebrain via Six3.