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Summary The mammalian brain undergoes sexual differentiation by gonadal hormones during the perinatal critical period. However, the machinery at earlier stages has not been well studied. We found that Ptf1a is expressed in certain neuroepithelial cells and immature neurons around the third ventricle that give rise to various neurons in several hypothalamic nuclei. We show that conditional Ptf1a -deficient mice ( Ptf1a cKO) exhibit abnormalities in sex-biased behaviors and reproductive organs in both sexes. Gonadal hormone administration to gonadectomized animals revealed that the abnormal behavior is caused by disorganized sexual development of the knockout brain. Accordingly, expression of sex-biased genes was severely altered in the cKO hypothalamus. In particular, Kiss1 , important for sexual differentiation of the brain, was drastically reduced in the cKO hypothalamus, which may contribute to the observed phenotypes in the Ptf1a cKO. These findings suggest that forebrain Ptf1a is one of the earliest regulators for sexual differentiation of the brain. [ABSTRACT FROM AUTHOR]

Summary Mutations in the Autism susceptibility candidate 2 gene ( AUTS2 ), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development. Immunohistochemistry and fractionation studies show that AUTS2 localizes not only in nuclei, but also in the cytoplasm, including in the growth cones in the developing brain. AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These findings suggest that cytoplasmic AUTS2 acts as a regulator of Rho family GTPases to contribute to brain development and give insight into the pathology of human psychiatric disorders with AUTS2 mutations. [ABSTRACT FROM AUTHOR]

Ptf1a, a basic helix-loop-helix transcription factor, plays an indispensable role for cell fate specification of subsets of neurons in the developing central nervous system. However, downstream molecules induced by Ptf1a during neural development have not been well characterized. In the present study, we identified immunoglobulin superfamily molecules, Nephrin and Neph3, as direct downstream targets of Ptf1a. First, the expression domains of Nephrin and Neph3 closely resembled those of Ptf1a in the developing retina, hypothalamus, cerebellum, hindbrain, and spinal cord. Second, Ptf1a bound directly to a PTF-binding motif in the 5′-flanking region of Nephrin and Neph3 genes. Third, Ptf1a activated transcription driven by the 5′-flanking region of these genes. Finally, the expression of Nephrin and Neph3 was lost in Ptf1a-null mice, whereas ectopic expression of Nephrin and Neph3 was induced by forced expression of Ptf1a. We provided further evidence that Nephrin and Neph3 could interact homophilically and heterophilically, suggesting that Nephrin and Neph3 might regulate certain developmental aspects of Ptf1a-positive neurons as homo- or heterooligomers. [ABSTRACT FROM AUTHOR]

STEF (Sif- and Tiam1-like exchange factor), a guanine nucleotide exchange factor, was identified as a candidate molecule in regulation of neural development. The STEF gene product specifically activates Rac1, a member of the Rho-like small G proteins. Here we report the detailed examination of the expression profile of the stef gene in the mouse brain. In situ hybridization revealed that the stef gene was expressed in a stage- and region-specific manner in the mouse brain; it was expressed during certain developmental stages in the cerebral cortex, the olfactory bulb, the rostral migratory pathway (RMP) and the hippocampus. In the cerebral cortex, stef transcripts were detected in migrating cells in the intermediate zone as well as neurons in the cortical plate. While the expression in the cerebral cortex was reduced at adult stages, considerable expression was found to be maintained in other regions (RMP, olfactory bulb, hippocampal formation), which are the tissues where neurons continue to undergo morphological remodeling including cellular migration, neurite extension and synapse formation even in adults. Thus, stef gene expression appears to correspond to neuronal morphological changes. [Copyright &y& Elsevier]

Development of oligodendrocytes, myelin-forming glia in the central nervous system (CNS), proceeds on a protracted schedule. Specification of oligodendrocyte progenitor cells (OPCs) begins early in development, whereas their terminal differentiation occurs at late embryonic and postnatal periods. However, for oligodendrocytes in the cerebellum, the developmental origins and the molecular machinery to control these distinct steps remain unclear. By in vivo fate mapping and immunohistochemical analyses, we obtained evidence that the majority of oligodendrocytes in the cerebellum originate from the Olig2-expressing neuroepithelial domain in the ventral rhombomere 1 (r1), while about 6% of cerebellar oligodendrocytes are produced in the cerebellar ventricular zone. Furthermore, to elucidate the molecular determinants that regulate their development, we analyzed mice in which the transcription factor Sox9 was specifically ablated from the cerebellum, ventral r1 and caudal midbrain by means of the Cre / loxP recombination system. This resulted in a delay in the birth of OPCs and subsequent developmental aberrations in these cells in the Sox9-deficient mice. In addition, we observed altered proliferation of OPCs, resulting in a decrease in oligodendrocyte numbers that accompanied an attenuation of the differentiation and an increased rate of apoptosis. Results from in vitro assays using oligodendrocyte-enriched cultures further supported our observations from in vivo experiments. These data suggest that Sox9 participates in the development of oligodendrocytes in the cerebellum, by regulating the timing of their generation, proliferation, differentiation and survival. [ABSTRACT FROM AUTHOR]