The mevalonate pathway is a crucial regulator of tendon cell specification.

Tendons and ligaments are crucial components of the musculoskeletal system, yet the pathways specifying these fates remain poorly defined. Through a screen of known bioactive chemicals in zebrafish, we identified a new pathway regulating tendon cell induction. We established that statin, through inhibition of the mevalonate pathway, causes an expansion of the tendon progenitor population. Co-expression and live imaging studies indicate that the expansion does not involve an increase in cell proliferation, but rather results from re-specification of cells from the neural crest-derived sox9a+/sox10+ skeletal lineage. The effect on tendon cell expansion is specific to the geranylgeranylation branch of the mevalonate pathway and is mediated by inhibition of Rac activity. This work establishes a novel role for the mevalonate pathway and Rac activity in regulating specification of the tendon lineage.

Strategic regulation of memory in dsyphoria: a quantity-accuracy profile analysis.

The mechanisms underlying a tendency among individuals with depression to report personal episodic memories with low specificity remain to be understood. We assessed a sample of undergraduate students with dysphoria to determine whether depression relates to a broader dysregulation of balancing accuracy and informativeness during memory reports. Specifically, we investigated metamnemonic processes using a quantity-accuracy profile approach. Recall involved three phases with increasing allowance for more general, or coarse-grained, responses: (a) forced-precise responding, requiring high precision; (b) free-choice report with high and low penalty incentives on accuracy; (c) a lexical description phase. Individuals with and without dysphoria were largely indistinguishable across indices of retrieval, monitoring, and control aspects of metamemory. The results indicate intact metacognitive processing in young individuals with dysphoria and provide no support for the view that impaired metacognitive control underlies either memory deficits or bias in memory reports that accompany dysphoria.

FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity.

Erythropoietin (EPO) signaling is critical to many processes essential to terminal erythropoiesis. Despite the centrality of iron metabolism to erythropoiesis, the mechanisms by which EPO regulates iron status are not well-understood. To this end, here we profiled gene expression in EPO-treated 32D pro-B cells and developing fetal liver erythroid cells to identify additional iron regulatory genes. We determined that FAM210B, a mitochondrial inner-membrane protein, is essential for hemoglobinization, proliferation, and enucleation during terminal erythroid maturation. Fam210b deficiency led to defects in mitochondrial iron uptake, heme synthesis, and iron-sulfur cluster formation. These defects were corrected with a lipid-soluble, small-molecule iron transporter, hinokitiol, in Fam210b-deficient murine erythroid cells and zebrafish morphants. Genetic complementation experiments revealed that FAM210B is not a mitochondrial iron transporter but is required for adequate mitochondrial iron import to sustain heme synthesis and iron-sulfur cluster formation during erythroid differentiation. FAM210B was also required for maximal ferrochelatase activity in differentiating erythroid cells. We propose that FAM210B functions as an adaptor protein that facilitates the formation of an oligomeric mitochondrial iron transport complex, required for the increase in iron acquisition for heme synthesis during terminal erythropoiesis. Collectively, our results reveal a critical mechanism by which EPO signaling regulates terminal erythropoiesis and iron metabolism.

CAT7 and cat7l Long Non-coding RNAs Tune Polycomb Repressive Complex 1 Function during Human and Zebrafish Development.

The essential functions of polycomb repressive complex 1 (PRC1) in development and gene silencing are thought to involve long non-coding RNAs (lncRNAs), but few specific lncRNAs that guide PRC1 activity are known. We screened for lncRNAs, which co-precipitate with PRC1 from chromatin and found candidates that impact polycomb group protein (PcG)-regulated gene expression in vivo A novel lncRNA from this screen, CAT7, regulates expression and polycomb group binding at the MNX1 locus during early neuronal differentiation. CAT7 contains a unique tandem repeat domain that shares high sequence similarity to a non-syntenic zebrafish analog, cat7l Defects caused by interference of cat7l RNA during zebrafish embryogenesis were rescued by human CAT7 RNA, enhanced by interference of a PRC1 component, and suppressed by interference of a known PRC1 target gene, demonstrating cat7l genetically interacts with a PRC1. We propose a model whereby PRC1 acts in concert with specific lncRNAs and that CAT7/cat7l represents convergent lncRNAs that independently evolved to tune PRC1 repression at individual loci.

Mutation mapping and identification by whole-genome sequencing.

Genetic mapping of mutations in model systems has facilitated the identification of genes contributing to fundamental biological processes including human diseases. However, this approach has historically required the prior characterization of informative markers. Here we report a fast and cost-effective method for genetic mapping using next-generation sequencing that combines single nucleotide polymorphism discovery, mutation localization, and potential identification of causal sequence variants. In contrast to prior approaches, we have developed a hidden Markov model to narrowly define the mutation area by inferring recombination breakpoints of chromosomes in the mutant pool. In addition, we created an interactive online software resource to facilitate automated analysis of sequencing data and demonstrate its utility in the zebrafish and mouse models. Our novel methodology and online tools will make next-generation sequencing an easily applicable resource for mutation mapping in all model systems.

Lower memory specificity in individuals with dysphoria is not specific to autobiographical memory.

BACKGROUND: A core cognitive attribute of depression is lower specificity in the expression of autobiographical memories. Despite interventions targeting memory specificity in depression, its underlying mechanisms are not yet fully understood. Depression also relates to poorer memory for episodic details; here we examine whether reduced specificity might simply reflect broader episodic memory deficits and weakened memory traces with the passage of time. METHODS: Undergraduate students with and without symptoms of depression completed the Autobiographical Interview and prose-reading episodic memory tasks to assess both same-day and delayed memory. RESULTS: Dysphoria and nondysphoria groups performed similarly on the tasks of immediate episodic and autobiographical memory; notably, the dysphoria group did not display evidence of lower specificity at this time point. After a delay, however, both groups demonstrated less specific memory responses on both memory tasks, and these declines were more pronounced in the group with dysphoria. That is, after a delay, individuals high in dysphoria showed a greater decrease in the quantity of specific event details reported on both the episodic and the autobiographical memory task. Additional analyses incorporating other clinical and cognitive measures indicated that these relations are largely unique to symptoms of depression. LIMITATIONS: The sample comprised mostly female students; the study should be replicated with more diverse samples. CONCLUSIONS: These findings support the claim that lower memory specificity is not peculiar to autobiographical memory, but rather, reflects impoverished memory more generally. This is an important consideration for theories and remedial strategies targeting memory specificity.

Episodic simulation of future events is impaired in patients with major depressive disorder.

We examined future episodic simulation in patients with major depressive disorder (MDD) using a method that distinguishes between episodic and non-episodic details of events. Patients were impaired at generating specific episodic details concerning future events; non-episodic details were not affected. In addition, all participants generated more episodic details for positive than for negative stimulus words. These results suggest a deficit in autonoetic awareness among patients with MDD. Difficulties imagining future events may impact upon the success of therapeutic interventions aimed at altering biases in the prediction of positive and negative future happenings.

Patients with bipolar disorder show a selective deficit in the episodic simulation of future events.

A substantial body of evidence suggests that autobiographical recollection and simulation of future happenings activate a shared neural network. Many of the neural regions implicated in this network are affected in patients with bipolar disorder (BD), showing altered metabolic functioning and/or structural volume abnormalities. Studies of autobiographical recall in BD reveal overgeneralization, where autobiographical memory comprises primarily factual or repeated information as opposed to details specific in time and in place and definitive of re-experiencing. To date, no study has examined whether these deficits extend to future event simulation. We examined the ability of patients with BD and controls to imagine positive, negative and neutral future events using a modified version of the Autobiographical Interview (Levine, Svoboda, Hay, Winocur, & Moscovitch, 2002) that allowed for separation of episodic and non-episodic details. Patients were selectively impaired in imagining future positive, negative, and neutral episodic details; simulation of non-episodic details was equivalent across groups.

The relationship between insight and autobiographical memory for emotional events in schizophrenia.

The relation of episodic and semantic memory for emotional- (positive, negative) and neutral-valenced autobiographical events to illness insight was examined in individuals with schizophrenia. Reduced recall of episodic details for negative events was significantly associated with impaired awareness of having a past mental disorder and its social consequences. Deficits in episodic memory for negative autobiographical events may underlie impaired insight in schizophrenia.

Impaired episodic memory for events encoded during mania in patients with bipolar disorder.

To date, very few studies have focused on autobiographical memory in patients with bipolar disorder. We examined whether mood state at the time of event encoding (i.e., manic, depressed, euthymic) influences subsequent recollection in these patients. We administered the Autobiographical Interview, a method that allowed us to dissociate episodic and semantic aspects of autobiographical memory. We also compared the memory perspective from which patients recollected these events. Patients were selectively impaired in recollecting episodic details of events encoded during mania but not depression or euthymia. No significant differences emerged between patients and controls for recollection of non-episodic details, regardless of mood state. Patients with bipolar disorder were also more likely than matched controls to recall memories from an observer perspective. These preliminary findings indicate a moderating influence of mood state at the time of event encoding on the subsequent recollection of autobiographical events in patients with bipolar disorder.

Spatial-memory deficit in schizophrenia spectrum disorders under viewpoint-independent demands in the virtual courtyard task.

This study builds upon our previous work indicating that impaired hippocampal-dependent forms of memory are core to schizophrenia. Using a virtual-reality courtyard task, we presented participants with schizophrenia spectrum disorders (SSD; n = 20) and a healthy community comparison group (n = 20) with objects to remember within a town square, followed by a recognition test of the location of objects from either the same viewpoint or a shifted viewpoint relative to initial presentation. The SSD group demonstrated a relative deficit under shifted- compared to same-view conditions. These findings provide further support for deficient hippocampal-dependent cognition in SSD.

Snx3 regulates recycling of the transferrin receptor and iron assimilation.

Sorting of endocytic ligands and receptors is critical for diverse cellular processes. The physiological significance of endosomal sorting proteins in vertebrates, however, remains largely unknown. Here we report that sorting nexin 3 (Snx3) facilitates the recycling of transferrin receptor (Tfrc) and thus is required for the proper delivery of iron to erythroid progenitors. Snx3 is highly expressed in vertebrate hematopoietic tissues. Silencing of Snx3 results in anemia and hemoglobin defects in vertebrates due to impaired transferrin (Tf)-mediated iron uptake and its accumulation in early endosomes. This impaired iron assimilation can be complemented with non-Tf iron chelates. We show that Snx3 and Vps35, a component of the retromer, interact with Tfrc to sort it to the recycling endosomes. Our findings uncover a role of Snx3 in regulating Tfrc recycling, iron homeostasis, and erythropoiesis. Thus, the identification of Snx3 provides a genetic tool for exploring erythropoiesis and disorders of iron metabolism.

A review of factors that moderate autobiographical memory performance in patients with major depressive disorder.

Studies of autobiographical recall in patients with major depressive disorder (MDD) reveal overgeneralization, where autobiographical memory (AM) comprises primarily factual or repeated information as opposed to details specific in time and in place and definitive of episodic re-experiencing. In addition to reviewing AM impairment in MDD, we explore the contribution of key method, demographic, and clinical variables to this dysfunction. Several candidate variables emerge, including testing method, emotion, mood state, illness burden, medication status, electroconvulsive therapy (ECT), comorbidity, trauma, age, ruminative state, and executive and memory function. These variables appear to interact in a complex manner to influence AM performance in MDD.