SUMMARY Alternative splicing is prevalent in the mammalian brain. To interrogate the functional role of alternative splicing in neural development, we analyzed purified neural progenitor cells (NPCs) and neurons from developing cerebral cortices, revealing hundreds of differentially spliced exons that preferentially alter key protein domains—especially in cytoskeletal proteins—and can harbor disease-causing mutations. We show that Ptbp1 and Rbfox proteins antagonistically govern the NPC-to-neuron transition by regulating neuron-specific exons. While Ptbp1 maintains apical progenitors partly through suppressing a poison exon of Flna in NPCs, Rbfox proteins promote neuronal differentiation by switching Ninein from a centrosomal splice form in NPCs to a non-centrosomal isoform in neurons. We further uncover an intronic human mutation within a PTBP1 binding site that disrupts normal skipping of the FLNA poison exon in NPCs and causes a brain-specific malformation. Our study indicates that dynamic control of alternative splicing governs cell fate in cerebral cortical development.

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The lumicrine system is a postulated signaling system in which testis-derived (upstream) secreted factors enter the male reproductive tract to regulate epididymal (downstream) pathways required for sperm maturation. Until now, no lumicrine factors have been identified. We demonstrate that a testicular germ-cell–secreted epidermal growth factor–like protein, neural epidermal growth factor–like–like 2 (NELL2), specifically binds to an orphan receptor tyrosine kinase, c-ros oncogene 1 (ROS1), and mediates the differentiation of the initial segment (IS) of the caput epididymis. Male mice in which Nell2 had been knocked out were infertile. The IS-specific secreted proteases, ovochymase 2 (OVCH2) and A disintegrin and metallopeptidase 28 (ADAM28), were expressed upon IS maturation, and OVCH2 was required for processing of the sperm surface protein ADAM3, which is required for sperm fertilizing ability. This work identifies a lumicrine system essential for testis-epididymis-spermatozoa (NELL2-ROS1-OVCH2-ADAM3) signaling and male fertility.

BackgroundThe first distinct differentiation event in mammals occurs at the blastocyst stage when totipotent blastomeres differentiate into either pluripotent inner cell mass (ICM) or multipotent trophectoderm (TE). Here we determined, for the first time, global gene expression patterns in the ICM and TE isolated from bovine blastocysts. The ICM and TE were isolated from blastocysts harvested at day 8 after insemination by magnetic activated cell sorting, and cDNA sequenced using the SOLiD 4.0 system.ResultsA total of 870 genes were differentially expressed between ICM and TE. Several genes characteristic of ICM (for example, NANOG, SOX2, and STAT3) and TE (ELF5, GATA3, and KRT18) in mouse and human showed similar patterns in bovine. Other genes, however, showed differences in expression between ICM and TE that deviates from the expected based on mouse and human.ConclusionAnalysis of gene expression indicated that differentiation of blastomeres of the morula-stage embryo into the ICM and TE of the blastocyst is accompanied by differences between the two cell lineages in expression of genes controlling metabolic processes, endocytosis, hatching from the zona pellucida, paracrine and endocrine signaling with the mother, and genes supporting the changes in cellular architecture, stemness, and hematopoiesis necessary for development of the trophoblast.

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We investigated the changes in follicular dynamics and steroidogenic activity during heat stress in goats. Adult female goats were exposed to heat stress at 36 8C and 70% relative humidity for 48 h and then injected with prostaglandin (PG) F 2a (the time of PGF 2a injection was designated as 0 h). In experiment 1, every follicle greater than 2 mm in diameter was monitored by ultrasonography to investigate the follicular dynamics, and plasma concentrations of FSH, LH, progesterone, and oestradiol were measured from 248 h to 120 h. In experiment 2, the follicles were recovered from the goats at 48 h, and the concentration of oestradiol, the aromatase activity, and the LH receptor level in the follicles were determined. In control (non-heatstressed) goats, ovulatory follicles were mainly recruited from 224 h to 0 h, whereas no follicles recruited during that period were ovulated in the heat-stressed goats. The timing of the recruitment of ovulatory follicles was delayed by heat stress by approximately 24 h. The plasma concentration of oestradiol in the heat-stressed goats was significantly lower from 36 to 54 h compared with the controls, although the concentrations of FSH and progesterone did not differ between the treatments. In addition, the concentration of oestradiol, the aromatase activity, and the LH receptor level in the follicles from heat-stressed goats were significantly lower compared with the controls. These results indicate that heat stress during follicular recruitment suppresses subsequent growth to ovulation, accompanied by decreased LH receptor level and oestradiol synthesis activity in the follicles.

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