The mammalian visual system, from retina to neocortex, has been extensively studied at both anatomical and functional levels. Anatomy indicates the cortico-thalamic system is hierarchical, but characterization of cellular-level functional interactions across multiple levels of this hierarchy is lacking, partially due to the challenge of simultaneously recording activity across numerous regions. Here, we describe a large, open dataset (part of the Allen Brain Observatory) that surveys spiking from units in six cortical and two thalamic regions responding to a battery of visual stimuli. Using spike cross-correlation analysis, we find that inter-area functional connectivity mirrors the anatomical hierarchy from the Allen Mouse Brain Connectivity Atlas. Classical functional measures of hierarchy, including visual response latency, receptive field size, phase-locking to a drifting grating stimulus, and autocorrelation timescale are all correlated with the anatomical hierarchy. Moreover, recordings during a visual task support the behavioral relevance of hierarchical processing. Overall, this dataset and the hierarchy we describe provide a foundation for understanding coding and dynamics in the mouse cortico-thalamic visual system..

The biological significance of RBCC (N-terminal RING finger/Bbox/coiled coil) proteins is increasingly being appreciated following demonstrated roles in disease pathogenesis, tumorigenesis, and retroviral protective activity. Found in all multicellular eukaryotes, RBCC proteins are involved in a vast array of intracellular functions; but as a general rule, they appear to function as part of large protein complexes and possess ubiquitin-protein isopeptide ligase activity. Those members characterized to date have diverse C-terminal domain compositions and equally diverse subcellular localizations and functions. Using a bioinformatics approach, we have identified some new RBCC proteins that help define a subfamily that shares an identical domain arrangement (MID1, MID2, TRIM9, TNL, TRIM36, and TRIFIC). Significantly, we show that all analyzed members of this subfamily associate with the microtubule cytoskeleton, suggesting that subcellular compartmentalization is determined by the unique domain architecture, which may in turn reflect basic functional similarities. We also report a new motif called the COS box, which is found within these proteins, the MURF family, and a distantly related non-RBCC microtubule-binding protein. Notably, we demonstrate that mutations in the COS box abolish microtubule binding ability, whereas its incorporation into a nonmicrotubule-binding RBCC protein redirects it to microtubule structures. Further bioinformatics investigation permitted subclassification of the entire human RBCC complement into nine subfamilies based on their varied C-terminal domain compositions. This classification schema may aid the understanding of the molecular function of members of each subgroup and their potential involvement in both basic cellular processes and human disease.Members of the RBCC (N-terminal RING finger/B-box/coiled coil) or TRIM (tripartite motif) family of proteins perform a diverse array of cellular roles, yet are believed to share some functional properties: 1) act as a scaffold for the assembly of larger multiprotein complexes and 2) possess RING-dependent ubiquitin ligase activity (1, 2). The RBCC domain can be found in isolation or in combination with a variety of other C-terminal domains, including the NHL (NCL-1/HT2A/LIN-41 repeat), immunoglobulin, MATH (meprin and tumor necrosis factor receptor-associated factor homology), B30.2-like/RFP (Ret finger protein)/SPRY (SplA and ryanodine receptor) (the largest subgroup in humans), ARF (ADP-ribosylation factor), PHD (plant homeodomain finger), and BROMO domains (1, 2). As a family of proteins, their biological significance is perhaps best highlighted by the growing number that have a demonstrated role in disease pathogenesis, including immunological and developmental disorders, tumorigenesis, and retroviral protective activity (3-7).We have previously identified and characterized two RBCC proteins, MID1 and its closely related homolog, MID2. MID1 and MID2 contain a B30.2-like domain at their C terminus and a single fibronectin type III (FN3...

Microtia is a congenital anomaly of the ear that ranges in severity from mild structural abnormalities to complete absence of the ear, and can occur as an isolated birth defect or as part of a spectrum of anomalies or a syndrome. Microtia is often associated with hearing loss and patients typically require treatment for hearing impairment and surgical ear reconstruction. The reported prevalence varies among regions, from 0.83 to 17.4 per 10,000 births and the prevalence is considered to be higher in Hispanics, Asians, Native Americans, and Andeans. The etiology of microtia and the cause of this wide variability in prevalence are poorly understood. Strong evidence supports the role of environmental and genetic causes for microtia. Although some studies have identified candidate genetic variants for microtia, no causal genetic mutation has been confirmed. The application of novel strategies in developmental biology and genetics has facilitated elucidation of mechanisms controlling craniofacial development. In this paper we review current knowledge of the epidemiology and genetics of microtia, including potential candidate genes supported by evidence from human syndromes and animal models. We also discuss the possible etiopathogenesis in light of the hypotheses formulated to date: neural crest cells disturbance, vascular disruption and altitude.

Recent studies have shown that exposure to some nutritional supplements and chemicals in utero can affect the epigenome of the developing mouse embryo, resulting in adult disease. Our hypothesis is that epigenetics is also involved in the gestational programming of adult phenotype by alcohol. We have developed a model of gestational ethanol exposure in the mouse based on maternal ad libitum ingestion of 10% (v/v) ethanol between gestational days 0.5–8.5 and observed changes in the expression of an epigenetically-sensitive allele, Agouti viable yellow (Avy), in the offspring. We found that exposure to ethanol increases the probability of transcriptional silencing at this locus, resulting in more mice with an agouti-colored coat. As expected, transcriptional silencing correlated with hypermethylation at Avy. This demonstrates, for the first time, that ethanol can affect adult phenotype by altering the epigenotype of the early embryo. Interestingly, we also detected postnatal growth restriction and craniofacial dysmorphology reminiscent of fetal alcohol syndrome, in congenic a/a siblings of the Avy mice. These findings suggest that moderate ethanol exposure in utero is capable of inducing changes in the expression of genes other than Avy, a conclusion supported by our genome-wide analysis of gene expression in these mice. In addition, offspring of female mice given free access to 10% (v/v) ethanol for four days per week for ten weeks prior to conception also showed increased transcriptional silencing of the Avy allele. Our work raises the possibility of a role for epigenetics in the etiology of fetal alcohol spectrum disorders, and it provides a mouse model that will be a useful resource in the continued efforts to understand the consequences of gestational alcohol exposure at the molecular level.

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