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Jackie A. Fretz, PhD

Research Associate 3 MS
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Additional Titles

Manager of Histology and Histomorphometry Laboratory, Orthopaedics & Rehabilitation

Contact Info

Yale School of Medicine

47 College Street, MORTHO

New Haven, CT 06510

United States

About

Titles

Research Associate 3 MS

Manager of Histology and Histomorphometry Laboratory, Orthopaedics & Rehabilitation

Biography

I obtained my BS in Biochemistry and Molecular Biology from the University of New Hampshire, and PhD in Biochemistry from the University of Wisconsin--Madison. My research career has focused on transcriptional regulation of cell fate. This has included NFATc1 in osteoclasts, the Vitamin D Receptor in osteoblasts, and EBF1 in mesenchymal progenitors.

Currently I am investigating the actions of EBF1 in mesenchymal progenitors and perivascular cells. In the bone this involves the actions of EBF1 in the vascular support cells (pericytes) to regulate bone vascularity, anabolism, and adipocyte differentiation. We have identified that the marrow adipocytes are a very different form of fat-storing cell than arises in other anatomical locations. This is primarily highlighted by the different way that these cells rely upon the presence of EBF1. Most interestingly Our investigations have revealed that EBF1 is essential to properly mobilize osteoblast progenitors into the bone lineage in the aging adult skeleton and following injury to mediate repair.

In the kidney EBF1 also participates in regulation of renal development and disease progression through it's ability of mesenchymal cells to modulate the vascularity of the glomerulus. Within the adult kidney podocytes use EBF1 to respond to glomerular injury and propagate sclerosis. Our work in kidney is also tied back to bone through the investigation of the pathology underlying chronic kidney disease-mineral bone disorders including regulation of FGF-23 in early chronic kidney disease.

Appointments

Education & Training

Research Scientist
Yale School of Medicine (2014)
Postdoctoral Fellowship
Yale School of Medicine (2011)
PhD
University of Wisconsin-Madison, Biochemistry (2007)
BS
University of New Hampshire, Biochemistry and Molecular Biology (2002)

Research

Overview

My research focuses on the role of the transcription factor (TF) Early B cell factor 1 (EBF1) in cellular fate determination and disease. EBF1 is one of four orthologous proteins that exist in vertebrates. This family of TFs is unique owing to the unusual structure of their DNA-binding domains. Working as homo-or hetero-dimers the EBF proteins contact DNA though an atypical zinc finger, and secondly through an IPT/TIG-like domain. Resultantly, they have an extremely flexible response element that makes in silico prediction of potential binding sites unreliable. Although EBF1 was named for its essential role in B cell lymphopoiesis, it has since been found to be essential to the formation and function of white adipose, neuronal subsets, vascular support populations, and as I discovered, kidney development. My research is focused on areas outside of the immune system where EBF1 is known to function; mesenchymal cell fate into the adipocyte lineage within the bone marrow contrasted against the peripheral adipose, and development and maintenance of the kidney glomerulus. As more is revealed about the actions of EBF1 in these disparate locations we are discovering that some conserved actions of EBF1 appear to be implicated in both processes.

EBF1 in Bone and Adipogenesis

I began working with EBF1 because this TF has an important role in the development of peripheral white adipose, where it promotes the mesenchymal transition to the adipocyte cell fate. We had originally hypothesized that EBF1 would participate in the formation of marrow adipose similarly to how it functions in peripheral white adipose (increasing bone density as progenitors were shunted away from the adipogenic fate to an osteoblastic one). Instead we were the first to report that EBF1-dependence proved to be a unique bifurcation point in cellular regulation that is not shared by these two adipocyte cell types. While EBF1 knockout mice are lipodystrophic with pronounced decreases in the perigonadal and mesenteric white depots, which are more heavily dependent upon EBF1 expression than subcutaneous depots, marrow fat formation is not inhibited and in fact increases. There is a very complex phenotype present in the global knockout mice that can cause non-cell intrinsic changes in marrow composition. Targeted deletion of EBF1 from the limb bud and all the mesenchymal lineage cells of the long bones results in bones that have marked changes in the bone vasculature and a pronounced increase in the number of marrow adipocytes present. We have traced this back to the pericyte subsets of the stroma and are currently identifying the transcriptional targets of EBF1 that make these marrow progenitors respond so differently than their peripheral white counterparts. At the same time there is an accumulation of marrow adipocytes that arise from these pericytes and a decrease in the commitment of these progenitors into the osteoblast lineage. Preliminary data suggest that the shift in lineage allocation may be a conserved consequence of EBF1 in these mesenchymal progenitors of both white adipose and in bone, and relate back to the direct function of EBF1 as a transcriptional regulator of SREBF1. I am submitting an R01 for this October deadline to the NIH to investigate these cells and the physiological consequences to the loss of EBF1.

In the peripheral white adipose I have discovered that in the absence of EBF1 white adipose is also resistant to the formation of metabolically favorable beige adipocytes. Interestingly, several stimuli that increase beigeing of the white fat also promote formation of marrow adipocytes, yet these two populations respond very differently to the absence of EBF1. In addition to an absence of entry into the beige cell fate my work discovered that peripheral white adipocytes lacking EBF1-expression are hypoproliferative, but also hypertrophic. EBF1 expression varies in peripheral adipose tissue in the human population. The consequence of this variation in expression is that those affected individuals with the lowest expression of EBF1 do not show significant change in body mass index, but do have hypertrophic adipocytes, display abrogated lipolysis, and are more insulin resistant than the individuals with normal EBF1 expression. We were also able to demonstrate that a conserved constellation of metabolic phenotypes (increased basal lipolysis, decreased stimulated lipolytic response, adipocyte hypertrophy and insulin resistance) occurs in global Ebf1 heterozygous mice. Mechanistic investigations that we have undertaken and which are still ongoing implicate EBF1 in the regulation of some key adipogenic receptors and proteins including the TF SREBP1 and beta-adrenergic receptors.

EBF1 in kidney glomerular function

My discovery of a role for EBF1 in the kidney arose from our investigations into its function in the bone. Paradoxically, the EBF1 global knockout mice had low bone density, but also exhibited high circulating levels of the anabolic marker Osteocalcin. Osteocalcin is normally an accurate marker of bone generation, until the integrity of the glomerular filtration barrier of the kidney is compromised. In the absence of EBF1 the mice have a congenital malformation of the glomerulus that results in renal failure. EBF1-deficient mice have thinned cortices, with poorly developed peripheral glomeruli and islands of undifferentiated mesenchyme that persist throughout adulthood. This was a discovery of a wholly novel role for EBF1 in physiology and development. Using targeted deletion our work has revealed that it is the mesangial cells and the stromal lineage (a mesenchymal derived cell population) that control capillary tuft branching. My research into EBF1 as an essential TF for proper maturation of the outer cortex and the glomerular tuft has revealed that EBF1 functions at the very last stages of capillary tuft development, a point of differentiation where the transcriptional and cytochemical processes involved are not well understood. It is interesting to note that both in the bone and in the kidney, although the exact consequence of the loss of EBF1 varies, both roles for EBF1 involve support and proliferation of an associated vascular network. Through investigation of the biological actions regulating EBF1 expression, and identification of the pathways affected by the actions of EBF1, I hope to better understand renal development and kidney disease with the goal of improving treatment strategies in the patient population afflicted with these debilitating and progressive conditions. This would be a valuable inroad for therapies because slowing and or reversal of glomerulosclerosis requires a resumption of capillary branching along with the resorption of fibrotic matrix. Investigation into the role of EBF1 in the regulation of the formation of this unique vascular bed will provide needed and still unknown insight into the processes that govern its formation.

Beyond this first action of EBF1 in the mesangial cell, we have also identified that there is a second role for this TF in the glomerular podocyte. Preliminary data from my laboratory has demonstrated that mice that lack EBF1 expression in only the podocytes are protected from kidney damage. While damage to all three types of glomerular cell can disrupt the filtration barrier, it is the limited potential of the podocyte to proliferate that is thought to precipitate sclerosis. EBF1 participates in the normal damage response of podocytes, and in its absence the podocytes are protected from effacement, sloughing, and consequently sclerosis. While we now understand that damage to and loss of podocytes from the capillary tuft is the event that precipitates glomerulosclerosis, the mechanisms controlling these processes are largely unknown. My pilot grant from the Yale O’Brien Center focused on identifying the relative protective contribution of EBF1 expression to the progression of glomerulosclerosis in both a rapidly progressing and slower acting but reversible model of glomerular injury, with the aim of identifying the signaling pathways and underlying biology employed by the podocyte to regulate both sclerotic progression and regression.

Connections between bone and kidney

There appears to be a conserved function of EBF1 between the bone and kidney where it is needed within mesenchymal vascular support cells in both locations. Interestingly, as we obtain more and more data from our injury models and the actions of EBF1 in adipogenic differentiation conserved metabolic pathways and key processes are consistently arising as transcriptional targets and downstream consequences of the loss of EBF1 in these non-immune cells. In fact, even our podocyte data has overlapping transcriptional targets and pathways that appear to be important for EBF1 regulation of beigeing as well as maintenance of podocyte integrity after kidney injury. These are molecular pathways that were not known at all to participate in the cellular processes that we are using EBF1 to investigate, and are opening new avenues to advance our understanding of these developmental processes and disease states regulated by EBF1.

Medical Subject Headings (MeSH)

Adipocytes; Bone and Bones; Bone Diseases; Bone Diseases, Metabolic; Chronic Kidney Disease-Mineral and Bone Disorder; Fractures, Ununited; Glomerular Filtration Rate; Glomerular Mesangium; Glomerulosclerosis, Focal Segmental; Juxtaglomerular Apparatus; Mesenchymal Stem Cells; Orthopedics; Osteoblasts; Pericytes; Podocytes; Transcriptional Activation

Research at a Glance

Yale Co-Authors

Frequent collaborators of Jackie A. Fretz's published research.

Publications

2024

2023

2020

2019

2017

2016

2015

  • Marrow Adipose Tissue and its Interactions with the Skeletal, Hematopoietic, and Immune Systems
    Berry R, Fretz JA, MacDougald O, Klibanski A, Rosen CJ, Rodeheffer M, Horowitz MC. (2015). Osteoimmunology: Interactions of the Immune and Skeletal Systems, 2nd edition. Elsevier 345-352. ISBN: 978-0-12-800571-2
    Peer-Reviewed Original Research

Academic Achievements & Community Involvement

  • activity

    Bone Marrow Sinusoidal Endothelial Cells Induce Fgf23 Expression During Iron Deficiency Anemia

  • honor

    ASBMR Mid-Career Travel grant

  • activity

    Marrow adiposity and vascular morphology are regulated by EBF1 in adult bone

  • activity

    The Tmprss6-/- Mouse Model of Iron Refractory Iron Deficiency Anemia (IRIDA) Exhibits Disrupted Phosphate Homeostasis, Elevated Circulating FGF23 Levels, and Increased Fgf23 Expression in Bone Marrow

  • activity

    Elevations in FGF-23 precede disruptions in either phosphate or iron homeostasis in the EBF1-KO model of renal insufficiency

Get In Touch

Contacts

Mailing Addresses

Yale School of Medicine

47 College Street, MORTHO

New Haven, CT 06510

United States

Yale School of Medicine

330 Cedar Cedar Street, Orthopaedics Histology Laboratory

New Haven, CT 06510

United States

Orthopaedic Histology and Histomorphometry Laboratory

200 South Frontage Road, Building FMB, Room 550, Attention: Jackie Fretz

New Haven, CT 06510

United States

Locations

  • Orthopaedics Histology and Histomorphometry Laboratory

    Lab

    Farnam Memorial Building (330 Cedar)

    330 Cedar Street, Rm 550

    New Haven, CT 06510

    General Information

    203.785.5136
  • Farnam Memorial Building (330 Cedar)

    Academic Office

    330 Cedar Street, Ste 550A

    New Haven, CT 06510

    General Information

    203.785.5136