Spatial restriction of alpha4 integrin phosphorylation regulates lamellipodial stability and alpha4beta1-dependent cell migration.

Integrins coordinate spatial signaling events essential for cell polarity and directed migration. Such signals from alpha4 integrins regulate cell migration in development and in leukocyte trafficking. Here, we report that efficient alpha4-mediated migration requires spatial control of alpha4 phosphorylation by protein kinase A, and hence localized inhibition of binding of the signaling adaptor, paxillin, to the integrin. In migrating cells, phosphorylated alpha4 accumulated along the leading edge. Blocking alpha4 phosphorylation by mutagenesis or by inhibition of protein kinase A drastically reduced alpha4-dependent migration and lamellipodial stability. alpha4 phosphorylation blocks paxillin binding in vitro; we now find that paxillin and phospho-alpha4 were in distinct clusters at the leading edge of migrating cells, whereas unphosphorylated alpha4 and paxillin colocalized along the lateral edges of those cells. Furthermore, enforced paxillin association with alpha4 inhibits migration and reduced lamellipodial stability. These results show that topographically specific integrin phosphorylation can control cell migration and polarization by spatial segregation of adaptor protein binding

Dynamics of dopamine signaling and network activity in the striatum during learning and motivated pursuit of goals

Thesis (Ph. D. in Neuroscience)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2013.Cataloged from PDF version of thesis. "February 2013."Includes bibliographical references (p. 118-126).Learning to direct behaviors towards goals is a central function of all vertebrate nervous systems. Initial learning often involves an exploratory phase, in which actions are flexible and highly variable. With repeated successful experience, behaviors may be guided by cues in the environment that reliably predict the desired outcome, and eventually behaviors can be executed as crystallized action sequences, or "habits", which are relatively inflexible. Parallel circuits through the basal ganglia and their inputs from midbrain dopamine neurons are believed to make critical contributions to these phases of learning and behavioral execution. To explore the neural mechanisms underlying goal-directed learning and behavior, I have employed electrophysiological and electrochemical techniques to measure neural activity and dopamine release in networks of the striatum, the principle input nucleus of the basal ganglia as rats learned to pursue rewards in mazes. The electrophysiological recordings revealed training dependent dynamics in striatum local field potentials and coordinated neural firing that may differentially support both network rigidity and flexibility during pursuit of goals. Electrochemical measurements of real-time dopamine signaling during maze running revealed prolonged signaling changes that may contribute to motivating or guiding behavior. Pathological over or under-expression of these network states may contribute to symptoms experienced in a range of basal ganglia disorders, from Parkinson's disease to drug addiction.by Mark W. Howe.Ph.D.in Neuroscienc

Differential Dynamics of Activity Changes in Dorsolateral and Dorsomedial Striatal Loops during Learning

The basal ganglia are implicated in a remarkable range of functions influencing emotion and cognition as well as motor behavior. Current models of basal ganglia function hypothesize that parallel limbic, associative, and motor cortico-basal ganglia loops contribute to this diverse set of functions, but little is yet known about how these loops operate and how their activities evolve during learning. To address these issues, we recorded simultaneously in sensorimotor and associative regions of the striatum as rats learned different versions of a conditional T-maze task. We found highly contrasting patterns of activity in these regions during task performance and found that these different patterns of structured activity developed concurrently, but with sharply different dynamics. Based on the region-specific dynamics of these patterns across learning, we suggest a working model whereby dorsomedial associative loops can modulate the access of dorsolateral sensorimotor loops to the control of action.National Institutes of Health (U.S.) (MH60379)United States. Office of Naval Research (N000140410208)Stanley H. and Sheila G. Sydney FundEuropean Union (Grant 201716)McGovern Institute for Brain Research at MIT (Fellowship

Spatial restriction of α4 integrin phosphorylation regulates lamellipodial stability and α4β1-dependent cell migration

Întegrins coordinate spatial signaling events essential for cell polarity and directed migration. Such signals from α4 integrins regulate cell migration in development and in leukocyte trafficking. Here, we report that efficient α4-mediated migration requires spatial control of α4 phosphorylation by protein kinase A, and hence localized inhibition of binding of the signaling adaptor, paxillin, to the integrin. In migrating cells, phosphorylated α4 accumulated along the leading edge. Blocking α4 phosphorylation by mutagenesis or by inhibition of protein kinase A drastically reduced α4-dependent migration and lamellipodial stability. α4 phosphorylation blocks paxillin binding in vitro; we now find that paxillin and phospho-α4 were in distinct clusters at the leading edge of migrating cells, whereas unphosphorylated α4 and paxillin colocalized along the lateral edges of those cells. Furthermore, enforced paxillin association with α4 inhibits migration and reduced lamellipodial stability. These results show that topographically specific integrin phosphorylation can control cell migration and polarization by spatial segregation of adaptor protein binding

Early childhood weight gain: Latent patterns and body composition outcomes.

BACKGROUND: Despite early childhood weight gain being a key indicator of obesity risk, we do not have a good understanding of the different patterns that exist. OBJECTIVES: To identify and characterise distinct groups of children displaying similar early-life weight trajectories. METHODS: A growth mixture model captured heterogeneity in weight trajectories between 0 and 60 months in 1390 children in the Avon Longitudinal Study of Parents and Children. Differences between the classes in characteristics and body size/composition at 9 years were investigated. RESULTS: The best model had five classes. The "Normal" (45%) and "Normal after initial catch-down" (24%) classes were close to the 50th centile of a growth standard between 24 and 60 months. The "High-decreasing" (21%) and "Stable-high" (7%) classes peaked at the ~91st centile at 12-18 months, but while the former declined to the ~75th centile and comprised constitutionally big children, the latter did not. The "Rapidly increasing" (3%) class gained weight from below the 50th centile at 4 months to above the 91st centile at 60 months. By 9 years, their mean body mass index (BMI) placed them at the 98th centile. This class was characterised by the highest maternal BMI; highest parity; highest levels of gestational hypertension and diabetes; and the lowest socio-economic position. At 9 years, the "Rapidly increasing" class was estimated to have 68.2% (95% confidence interval [CI] 48.3, 88.1) more fat mass than the "Normal" class, but only 14.0% (95% CI 9.1, 18.9) more lean mass. CONCLUSIONS: Criteria used in growth monitoring practice are unlikely to consistently distinguish between the different patterns of weight gain reported here

Distinct Body Mass Index Trajectories to Young-Adulthood Obesity and Their Different Cardiometabolic Consequences.

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Unique contributions of parvalbumin and cholinergic interneurons in organizing striatal networks during movement

Published in final edited form as: Nat Neurosci. 2019 April ; 22(4): 586–597. doi:10.1038/s41593-019-0341-3.Striatal pavalbumin (PV) and cholinergic (CHI) interneurons are poised to play major roles in behavior by coordinating the networks of medium spiny cells that relay motor output. However, the small numbers and scattered distribution of these cells has made it difficult to directly assess their contribution to activity in networks of MSNs during behavior. Here, we build upon recent improvements in single cell calcium imaging combined with optogenetics to test the capacity of PVs and CHIs to affect MSN activity and behavior in mice engaged in voluntarily locomotion. We find that PVs and CHIs have unique effects on MSN activity and dissociable roles in supporting movement. PV cells facilitate movement by refining the activation of MSN networks responsible for movement execution. CHIs, in contrast, synchronize activity within MSN networks to signal the end of a movement bout. These results provide new insights into the striatal network activity that supports movement.Accepted manuscrip

Canonical Wnt signals combined with suppressed TGFβ/BMP pathways promote renewal of the native human colonic epithelium

Background: A defining characteristic of the human intestinal epithelium is that it is the most rapidly renewing tissue in the body. However, the processes underlying tissue renewal and the mechanisms that govern their coordination have proved difficult to study in the human gut. Objective: To investigate the regulation of stem cell-driven tissue renewal by canonical Wnt and TGFβ/bone morphogenetic protein (BMP) pathways in the native human colonic epithelium. Design: Intact human colonic crypts were isolated from mucosal tissue samples and placed into 3D culture conditions optimised for steady-state tissue renewal. High affinity mRNA in situ hybridisation and immunohistochemistry were complemented by functional genomic and bioimaging techniques. The effects of signalling pathway modulators on the status of intestinal stem cell biology, crypt cell proliferation, migration, differentiation and shedding were determined. Results: Native human colonic crypts exhibited distinct activation profiles for canonical Wnt, TGFβ and BMP pathways. A population of intestinal LGR5/OLFM4-positive stem/progenitor cells were interspersed between goblet-like cells within the crypt-base. Exogenous and crypt cell-autonomous canonical Wnt signals supported homeostatic intestinal stem/progenitor cell proliferation and were antagonised by TGFβ or BMP pathway activation. Reduced Wnt stimulation impeded crypt cell proliferation, but crypt cell migration and shedding from the crypt surface were unaffected and resulted in diminished crypts. Conclusions: Steady-state tissue renewal in the native human colonic epithelium is dependent on canonical Wnt signals combined with suppressed TGFβ/BMP pathways. Stem/progenitor cell proliferation is uncoupled from crypt cell migration and shedding, and is required to constantly replenish the crypt cell population

The genome sequence of the European golden eagle, Aquila chrysaetos chrysaetos Linnaeus 1758.

We present a genome assembly from an individual female Aquila chrysaetos chrysaetos (the European golden eagle; Chordata; Aves; Accipitridae). The genome sequence is 1.23 gigabases in span. The majority of the assembly is scaffolded into 28 chromosomal pseudomolecules, including the W and Z sex chromosomes

The genome sequence of the Norway rat, Rattus norvegicus Berkenhout 1769.

We present a genome assembly from an individual male Rattus norvegicus (the Norway rat; Chordata; Mammalia; Rodentia; Muridae). The genome sequence is 2.44 gigabases in span. The majority of the assembly is scaffolded into 20 chromosomal pseudomolecules, with both X and Y sex chromosomes assembled. This genome assembly, mRatBN7.2, represents the new reference genome for R. norvegicus and has been adopted by the Genome Reference Consortium