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The transition to multicellularity has occurred numerous times in all domains of life, yet its initial steps are poorly understood. The volvocine green algae are a tractable system for understanding the genetic basis of multicellularity including the initial formation of cooperative cell groups. Here we report the genome sequence of the undifferentiated colonial alga, Gonium pectorale, where group formation evolved by co-option of the retinoblastoma cell cycle regulatory pathway. Significantly, expression of the Gonium retinoblastoma cell cycle regulator in unicellular Chlamydomonas causes it to become colonial. The presence of these changes in undifferentiated Gonium indicates extensive group-level adaptation during the initial step in the evolution of multicellularity. These results emphasize an early and formative step in the evolution of multicellularity, the evolution of cell cycle regulation, one that may shed light on the evolutionary history of other multicellular innovations and evolutionary transitions. The undifferentiated Gonium pectorale represents the initial transition to multicellularity. Here, Bradley Olson, Erik Hanschen and colleagues describe the genome of Gonium pectorale , demonstrating that co-option of the retinoblastoma cell cycle regulatory pathway was a key genetic change in the evolution of multicellularity.

The routes of hair growth Hair follicle miniaturization is a degenerative process that reduces the dimensions of the epithelial and mesenchymal cell compartments, converting thick hair to fine, downy hair. It is most commonly observed in androgenetic alopecia, but is also characteristic of a rare form of hair loss known as hereditary hypotrichosis simplex (HHS). The gene involved in HHS has now been identified by genetic linkage analysis in affected families as APCDD1 , which encodes a membrane-bound glycoprotein abundantly expressed in human hair follicles. Functional studies show that APCDD1 inhibits Wnt signalling, and is thus a potentially important component of signal transduction pathways in the hair follicle. Hereditary hypotrichosis simplex is a rare form of hereditary hair loss in humans, where the hair follicle is miniaturized. Now, the gene involved has been identified, using genetic linkage analysis in three affected families. The gene, APCDD1 , is expressed in human hair follicles. It encodes a previously unknown membrane-bound glycoprotein that inhibits signalling through the Wnt protein and functions upstream of β-catenin. Hereditary hypotrichosis simplex is a rare autosomal dominant form of hair loss characterized by hair follicle miniaturization 1 , 2 . Using genetic linkage analysis, we mapped a new locus for the disease to chromosome 18p11.22, and identified a mutation (Leu9Arg) in the adenomatosis polyposis down-regulated 1 ( APCDD1 ) gene in three families. We show that APCDD1 is a membrane-bound glycoprotein that is abundantly expressed in human hair follicles, and can interact in vitro with WNT3A and LRP5—two essential components of Wnt signalling. Functional studies show that APCDD1 inhibits Wnt signalling in a cell-autonomous manner and functions upstream of β-catenin. Moreover, APCDD1 represses activation of Wnt reporters and target genes, and inhibits the biological effects of Wnt signalling during both the generation of neurons from progenitors in the developing chick nervous system, and axis specification in Xenopus laevis embryos. The mutation Leu9Arg is located in the signal peptide of APCDD1, and perturbs its translational processing from the endoplasmic reticulum to the plasma membrane. APCDD1(L9R) probably functions in a dominant-negative manner to inhibit the stability and membrane localization of the wild-type protein. These findings describe a novel inhibitor of the Wnt signalling pathway with an essential role in human hair growth. As APCDD1 is expressed in a broad repertoire of cell types 3 , our findings indicate that APCDD1 may regulate a diversity of biological processes controlled by Wnt signalling.

Receptor tyrosine kinase EphB2 mediates development of the neurogenic niche of excitatory neurons, suggesting the possibility that its inactivation plays a role in neuropsychiatric disorders including depression and memory impairment. While N-methyl-D-aspartate (NMDA) receptor is involved in regulating memory formation and neurogenesis in adult animal, it remains unclear how NMDA receptor subtypes mediate depression and cognitive deficits caused by EphB2 loss. The present study shows that EphB2 inactivation results in depression-like behaviors, memory impairment and defects of adult hippocampal neurogenesis. Compared to wild-type littermates, EphB2 KO mice exhibited depression-like behavior and deficits in spatial memory and cognition in forced swimming, tail suspension, Morris water maze, object recognition test and object location test. These behavioral abnormalities were accompanied by substantial decreases in the number of BrdU+ progenitor neurons, phosphorylation of cAMP-response element binding protein (pCREB) and brain derived neurotrophic factor (BDNF), and increased NMDA receptor 2B (NR2B) expression. These molecular, cellular and behavioral alterations induced by EphB2 inactivation were reversed by NR2B antagonist Ro25-6981, suggesting that EphB2 functions to prevent the progression of depression-like behavior and memory impairment by downregulating NR2B. Our findings highlight that NR2B is responsible for EphB2-dependent behavioral and morphological changes. EphB2 may thus be as an important candidate target for treating psychiatric and cognitive disorders.

Background: Major depressive disorder (MDD) is a severe mental disorder related to the deficiency of monoamine neurotransmitters, particularly to abnormalities of 5-HT (5-hydroxytryptamine, serotonin) and its receptors. Our previous study suggested that acute treatment with a novel curcumin derivative J147 exhibited antidepressant-like effects by increasing brain derived neurotrophic factor (BDNF) level in the hippocampus of mice. The present study expanded upon our previous findings and investigated the antidepressant-like effects of sub-acute treatment of J147 for 3 days in male ICR mice and its possible relevancy to 5-HT1A and 5-HT1B receptors and downstream cAMP-BDNF signaling. Methods: J147 at doses of 1, 3 and 9 mg/kg (via gavage) was administered for 3 days and the anti-immobility time in the forced swimming and tail suspension tests (FST and TST) was recorded. The radioligand binding assay was used to determine the affinity of J147 to 5-HT1A and 5-HT1B receptor. Moreover, 5-HT1A or 5-HT1B agonist or its antagonist was used to determine which 5-HT receptor subtype is involved in the antidepressant-like effects of J147. The downstream signaling molecules such as cAMP, PKA, pCREB and BDNF were also measured to determine the mechanism of action. Results: The results demonstrated that sub-acute treatment of J147 remarkably decreased the immobility time in both the FST and TST in a dose-dependent manner. J147 displayed high affinity in vitro to 5-HT1A receptor prepared from mice cortical tissue and was less potent at 5-HT1B receptor. These effects of J147 were blocked by pretreatment with a 5-HT1A antagonist NAD-299 and enhanced by a 5-HT1A agonist 8-OH-DPAT. However, 5-HT1B receptor antagonist NAS-181 did not appreciably alter the effects of J147 on depression-like behaviors. Moreover, pretreatment with NAD-299 blocked J147-induced increases in cAMP, PKA, pCREB and BDNF expression in the hippocampus. While 8-OH-DPAT enhanced the effects of J147 on these proteins’ expression. Conclusion: The results suggest that J147 induces rapid antidepressant-like effects during a 3-day treatment period without inducing drug tolerance. These effects might be mediated by 5-HT1A dependent cAMP/PKA/pCREB/BDNF signaling.

Background Unique among cnidarians, jellyfish have remarkable morphological and biochemical innovations that allow them to actively hunt in the water column and were some of the first animals to become free-swimming. The class Scyphozoa, or true jellyfish, are characterized by a predominant medusa life-stage consisting of a bell and venomous tentacles used for hunting and defense, as well as using pulsed jet propulsion for mobility. Here, we present the genome of the giant Nomura’s jellyfish ( Nemopilema nomurai ) to understand the genetic basis of these key innovations. Results We sequenced the genome and transcriptomes of the bell and tentacles of the giant Nomura’s jellyfish as well as transcriptomes across tissues and developmental stages of the Sanderia malayensis jellyfish. Analyses of the Nemopilema and other cnidarian genomes revealed adaptations associated with swimming, marked by codon bias in muscle contraction and expansion of neurotransmitter genes, along with expanded Myosin type II family and venom domains, possibly contributing to jellyfish mobility and active predation. We also identified gene family expansions of Wnt and posterior Hox genes and discovered the important role of retinoic acid signaling in this ancient lineage of metazoans, which together may be related to the unique jellyfish body plan (medusa formation). Conclusions Taken together, the Nemopilema jellyfish genome and transcriptomes genetically confirm their unique morphological and physiological traits, which may have contributed to the success of jellyfish as early multi-cellular predators.

BackgroundNeuronal topographic map formation requires appropriate selection of axonal trajectories at intermediate choice points prior to target innervation. Axons of neurons in the spinal cord lateral motor column (LMC), as defined by a transcription factor code, are thought to innervate limb target tissues exclusively. Axons of the medial and lateral LMC divisions appear to execute a binary decision at the base of the limb as they choose between ventral and dorsal limb trajectories. The cellular logic that guides motor axon trajectory choices into non-limb tissues such as the ventral flank remains unclear.ResultsWe determined the spinal cord motor column origin of motor nerves that innervate ventral flank tissues at hindlimb level. We found unexpectedly that a subset of medial LMC axons innervates ventral non-limb mesenchyme at hindlimb level, rather than entering ventral limb mesenchyme. We also found that in a conditional BmprIa mutant where all ventral hindlimb mesenchyme is converted to a dorsal identity, all medial LMC axons are redirected into the ventral flank, while lateral LMC axons innervate the bidorsal limb.ConclusionWe have found that medial LMC neurons innervate both ventral flank and limb targets. While normally only a subset of medial LMC axons innervate the flank, all are capable of doing so. Furthermore, LMC axons execute a ternary, rather than binary, choice at the base of the limb between ventral flank, ventral limb and dorsal limb trajectories. When making this choice, medial and lateral LMC axons exhibit different and asymmetric relative preferences for these three trajectories. These data redefine the LMC as a motor column that innervates both limb and body tissues.

A transgenic mouse strain with early and uniform expression of the Cre site-specific recombinase is described. In this strain, PGK-Crem, Cre is driven by the early acting PGK-1 promoter, but, probably due to cis effects at the integration site, the recombinase is under dominant maternal control. When Cre is transmitted by PGK-Crem females mated to males that carry a reporter transgene flanked by loxP sites, even offspring that do not inherit PGK-Cre delete the target gene. It follows that in the PGK-Crem female Cre activity commences in the diploid phase of oogenesis. In PGK-Crem crosses complete recombination was observed in all organs, including testis and ovary. We prepared a mouse stock that is homozygous for PGK-Crem and at the albino (c) locus. This strain will be useful for the early and uniform induction of ectopic and dominant negative mutations, for the in vivo removal of selective elements from targeted mutations and in connection with the manipulation of targeted loci in 'knock in' and related technologies.

The precise regulation of gene expression is fundamental to neurodevelopment, plasticity and cognitive function. Although several studies have profiled transcription in the developing human brain, there is a gap in understanding of accompanying translational regulation. In this study, we performed ribosome profiling on 73 human prenatal and adult cortex samples. We characterized the translational regulation of annotated open reading frames (ORFs) and identified thousands of previously unknown translation events, including small ORFs that give rise to human-specific and/or brain-specific microproteins, many of which we independently verified using proteomics. Ribosome profiling in stem-cell-derived human neuronal cultures corroborated these findings and revealed that several neuronal activity-induced non-coding RNAs encode previously undescribed microproteins. Physicochemical analysis of brain microproteins identified a class of proteins that contain arginine-glycine-glycine (RGG) repeats and, thus, may be regulators of RNA metabolism. This resource expands the known translational landscape of the human brain and illuminates previously unknown brain-specific protein products.Duffy et al. profiled mRNA translation in 73 human prenatal and adult cortex samples and identified thousands of previously unknown translation events, including small open reading frames that give rise to human-specific and/or brain-specific microproteins.

Although genomic analyses predict many noncanonical open reading frames (ORFs) in the human genome, it is unclear whether they encode biologically active proteins. Here we experimentally interrogated 553 candidates selected from noncanonical ORF datasets. Of these, 57 induced viability defects when knocked out in human cancer cell lines. Following ectopic expression, 257 showed evidence of protein expression and 401 induced gene expression changes. Clustered regularly interspaced short palindromic repeat (CRISPR) tiling and start codon mutagenesis indicated that their biological effects required translation as opposed to RNA-mediated effects. We found that one of these ORFs, G029442 —renamed g lycine-rich extracellular protein-1 (GREP1)—encodes a secreted protein highly expressed in breast cancer, and its knockout in 263 cancer cell lines showed preferential essentiality in breast cancer-derived lines. The secretome of GREP1-expressing cells has an increased abundance of the oncogenic cytokine GDF15, and GDF15 supplementation mitigated the growth-inhibitory effect of GREP1 knockout. Our experiments suggest that noncanonical ORFs can express biologically active proteins that are potential therapeutic targets. Noncanonical open reading frames are shown to be essential for cancer cell function.

The endangered whale shark (Rhincodon typus) is the largest fish on Earth and a long-lived member of the ancient Elasmobranchii clade. To characterize the relationship between genome features and biological traits, we sequenced and assembled the genome of the whale shark and compared its genomic and physiological features to those of 83 animals and yeast. We examined the scaling relationships between body size, temperature, metabolic rates, and genomic features and found both general correlations across the animal kingdom and features specific to the whale shark genome. Among animals, increased lifespan is positively correlated to body size and metabolic rate. Several genomic traits also significantly correlated with body size, including intron and gene length. Our large-scale comparative genomic analysis uncovered general features of metazoan genome architecture: Guanine and cytosine (GC) content and codon adaptation index are negatively correlated, and neural connectivity genes are longer than average genes in most genomes. Focusing on the whale shark genome, we identified multiple features that significantly correlate with lifespan. Among these were very long gene length, due to introns being highly enriched in repetitive elements such as CR1-like long interspersed nuclear elements, and considerably longer neural genes of several types, including connectivity, activity, and neurodegeneration genes. The whale shark genome also has the second slowest evolutionary rate observed in vertebrates to date. Our comparative genomics approach uncovered multiple genetic features associated with body size, metabolic rate, and lifespan and showed that the whale shark is a promising model for studies of neural architecture and lifespan.