Transforming growth factor-beta renders ageing microglia inhibitory to oligodendrocyte generation by CNS progenitors.

It is now well-established that the macrophage and microglial response to CNS demyelination influences remyelination by removing myelin debris and secreting a variety of signaling molecules that influence the behaviour of oligodendrocyte progenitor cells (OPCs). Previous studies have shown that changes in microglia contribute to the age-related decline in the efficiency of remyelination. In this study, we show that microglia increase their expression of the proteoglycan NG2 with age, and that this is associated with an altered micro-niche generated by aged, but not young, microglia that can divert the differentiation OPCs from oligodendrocytes into astrocytes in vitro. We further show that these changes in ageing microglia are generated by exposure to high levels of TGFβ. Thus, our findings suggest that the rising levels of circulating TGFβ known to occur with ageing contribute to the age-related decline in remyelination by impairing the ability of microglia to promote oligodendrocyte differentiation from OPCs, and therefore could be a potential therapeutic target to promote remyelination.This work was supported by funding from the UK Multiple Sclerosis Society, Medimmune, The Adelson Medical Research Foundation and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institut

The Grizzly, November 4, 1988

Continued Controversy Plagues Campus • Division III\u27s Founding Athletics • Curriculum IDEAS Fire Faculty • Drive to be Closed • Letter: Guilty Till Proven Innocent: Democracy at Ursinus College • Conference a Great Success • Bear Pack Braces for Title Run • Seniors are Class of Hockey • Career Day to be Sponsored for Campus • Security Moves to Reimert • French Presents Finzihttps://digitalcommons.ursinus.edu/grizzlynews/1222/thumbnail.jp

Complement Targets Newborn Retinal Ganglion Cells for Phagocytic Elimination by Microglia

Microglia play important roles in shaping the developing CNS, and at early stages they have been proposed to regulate progenitor proliferation, differentiation, and neuronal survival. However, these studies reveal contradictory outcomes, highlighting the complexity of these cell-cell interactions. Here, we investigate microglia function during embryonic mouse retina development, where only microglia, progenitors, and neurons are present. In both sexes, we determine that microglia primarily interact with retinal neurons and find that depletion of microglia via conditional KO of the Csf1 receptor results in increased density of retinal ganglion cells (RGCs). Pharmacological inhibition of microglia also results in an increase in RGCs, with no effect on retinal progenitor proliferation, RGC genesis, or apoptosis. We show that microglia in the embryonic retina are enriched for phagocytic markers and observe engulfment of nonapoptotic Brn3-labeled RGCs. We investigate the molecular pathways that can mediate cell engulfment by microglia and find selective downregulation of complement pathway components with microglia inhibition, and further show that C1q protein marks a subset of RGCs in the embryonic retina. KO of complement receptor 3 (CR3; Itgam), which is only expressed by microglia, results in increased RGC density, similar to what we observed after depletion or inhibition of microglia. Thus, our data suggest that microglia regulate neuron elimination in the embryonic mouse retina by complement-mediated phagocytosis of non-apoptotic newborn RGCs. SIGNIFICANCE STATEMENT Microglia are emerging as active and important participants in regulating neuron number in development, during adult neurogenesis, and following stem cell therapies. However, their role in these contexts and the mechanisms involved are not fully defined. Using a well-characterized in vivo system, we provide evidence that microglia regulate neuronal elimination by complement-mediated engulfment of nonapoptotic neurons. This work provides a significant advancement of the field by defining in vivo molecular mechanisms for microglia-mediated cell elimination. Our data add to a growing body of evidence that microglia are essential for proper nervous system development. In addition, we elucidate microglia function in the developing retina, which may shed light on microglia involvement in the context of retinal injury and disease

The Grizzly, September 1, 1989

U.C. Transition • Diverse Freshman Diverge on Ursinus • Letter: Frosh Finds Staff Discourteous • Corson Facelift Removes Moles • Bright Moments Jazz Steams Bomberger Night • Bio Grants Lend Expansion • Lax: National Champs! • Wood Takes Titles • Lacrosse Coaches Retire • Lady Bears: Few, But Strong • Bears to Repeat • St. Joe\u27s / U.C. MBA Still O.K. • Academic Year Openedhttps://digitalcommons.ursinus.edu/grizzlynews/1238/thumbnail.jp

A developmental analysis of juxtavascular microglia dynamics and interactions with the vasculature [preprint]

Microglia, the resident macrophages of the central nervous system (CNS), are dynamic cells, constantly extending and retracting their processes as they contact and functionally regulate neurons and other glial cells. There is far less known about microglia-vascular interactions, particularly under healthy steady-state conditions. Here, we use the male and female mouse cerebral cortex to show that a higher percentage of microglia associate with the vasculature during the first week of postnatal development compared to older ages and the timing of these associations are dependent on the fractalkine receptor (CX3CR1). Similar developmental microglia-vascular associations were detected in the prenatal human brain. Using live imaging in mice, we found that juxtavascular microglia migrated when microglia are actively colonizing the cortex and became stationary by adulthood to occupy the same vascular space for nearly 2 months. Further, juxtavascular microglia at all ages contact vascular areas void of astrocyte endfeet and the developmental shift in microglial migratory behavior along vessels corresponded to when astrocyte endfeet more fully ensheath vessels. Together, our data provide a comprehensive assessment of microglia-vascular interactions. They support a mechanism by which microglia use the vasculature to migrate within the developing brain parenchyma. This migration becomes restricted upon the arrival of astrocyte endfeet when juxtavascular microglia then establish a long-term, stable contact with the vasculature

A Developmental Analysis of Juxtavascular Microglia Dynamics and Interactions with the Vasculature

Microglia, a resident CNS macrophage, are dynamic cells, constantly extending and retracting their processes as they contact and functionally regulate neurons and other glial cells. There is far less known about microglia-vascular interactions, particularly under healthy steady-state conditions. Here, we use the male and female mouse cerebral cortex to show that a higher percentage of microglia associate with the vasculature during the first week of postnatal development compared with older ages and that the timing of these associations is dependent on the fractalkine receptor (CX3CR1). Similar developmental microglia-vascular associations were detected in the human brain. Using live imaging in mice, we found that juxtavascular microglia migrated when microglia are actively colonizing the cortex and became stationary by adulthood to occupy the same vascular space for nearly 2 months. Further, juxtavascular microglia at all ages associate with vascular areas void of astrocyte endfeet, and the developmental shift in microglial migratory behavior along vessels corresponded to when astrocyte endfeet more fully ensheath vessels. Together, our data provide a comprehensive assessment of microglia-vascular interactions. They support a mechanism by which microglia use the vasculature to migrate within the developing brain parenchyma. This migration becomes restricted on the arrival of astrocyte endfeet such that juxtavascular microglia become highly stationary and stable in the mature cortex. SIGNIFICANCE STATEMENT We report the first extensive analysis of juxtavascular microglia in the healthy, developing, and adult brain. Live imaging revealed that juxtavascular microglia within the cortex are highly motile and migrate along vessels as they are colonizing cortical regions. Using confocal, expansion, super-resolution, and electron microscopy, we determined that microglia associate with the vasculature at all ages in areas lacking full astrocyte endfoot coverage and motility of juxtavascular microglia ceases as astrocyte endfeet more fully ensheath the vasculature. Our data lay the fundamental groundwork to investigate microglia-astrocyte cross talk and juxtavascular microglial function in the healthy and diseased brain. They further provide a potential mechanism by which vascular interactions facilitate microglial colonization of the brain to later regulate neural circuit development

The Grizzly, October 14, 1988

Task Force Committee Trims Curriculum • Gender, Class and Race Addressed at Conference • Awareness Week on the Wagon • Letters: Some Sobering Thoughts for Students; Interdepartmental Cooperation Stressed • And the Band Played On... • A Voice of My Own to Air • Wellness Week Results • Rice Cooks Up Recipe for Art • Bears Take Homecoming Thriller in Final :33 • Soccer Kicks Into Winning Gear • X-Country Runs \u27Round Alumni • Hockey Unpredictablehttps://digitalcommons.ursinus.edu/grizzlynews/1220/thumbnail.jp

The Grizzly, May 2, 1989

Greeks Grab Spotlight • Grad. Speakers Tapped • Benedict No.1 • Letter: Racism! Not Just Rednecks • Williams\u27 Farewell • Richter Honored • ISIC\u27s for Going Abroad • The Arena: Seeking Opinions • Trenton Draws First Blood • U.C. Hits Stumbling Block • Positive for MAC\u27s • Crabs and Fries: The Spice of Life • Dance Marathon Coming • Senior Altruism Needed • Seniors\u27 Lasting Impressions: Your Most Memorable Moments at U.C.? • Final Exam Schedulehttps://digitalcommons.ursinus.edu/grizzlynews/1237/thumbnail.jp

The Grizzly, November 11, 1988

Bush Takes Election: Republicans Win Four More • Students Voice Concerns: Richter and Kane Listen • Letter: Beam The Grizzly Up, Billy • Finzi\u27s French\u27s Forte • College\u27s Music Program Reviewed • The Pack is Back with 5th MAC Title • Ladies Take Seventh • \u27Mers Open Season • Soccer Booted in ECAC • The Grizzly Presents our Champion Team • Red and Gold Days: A Big Hit • Presenting Women\u27s Achievementhttps://digitalcommons.ursinus.edu/grizzlynews/1223/thumbnail.jp

The Grizzly, November 18, 1988

Booze Ban - No Bomb - But No New Booze News • Hess Awarded Honorary Chair • Talent Show Dazzles Ursinus Community • Letters: Alumnus Voices Drug Concerns; Stuff it in Your Socks, Mr. Bill • Escape with Chiapparone • Meehan, U.C. Spoil Dickinson\u27s Party • Pack Takes 3rd; O\u27Donohue Makes Nationals • Matters Fare Well at LaSalle Tourney • Circle Up with Circle K • Hoopsters Open with Cautious Optimismhttps://digitalcommons.ursinus.edu/grizzlynews/1224/thumbnail.jp