Life Sciences Research for Lifelong Health

Heidi Welch

Research Summary

We study molecular mechanisms that control the Rac protein family, which regulates cell shape, cell movement, oxygen radical formation and gene expression. In particular, we study the proteins that activate Rac, so-called Rac-GEFs. A few years ago, we discovered a new type of Rac-GEF, the P-Rex family, and we have been studying the mechanisms that regulate their activity and their functional roles.

We found that P-Rex family Rac-GEFs are important for the ability of our white blood cells to defend us against bacterial and fungal infections, for the shape and electrical functions of nerve cells that control the coordination of our movements, and for the distribution of skin pigment cells during development. We also participated in studies which showed that the deregulation of the cellular amount or activity of P-Rex family Rac-GEFs contribute to cancer growth and metastasis.

Currently, our lab is investigating new functional roles of P-Rex and other Rac-GEFs, particularly in inflammatory cells, and we are inventing new ways of monitoring Rac-GEF activity.

Latest Publications

Removing physiological motion from intravital and clinical functional imaging data.
Warren SC, Nobis M, Magenau A, Mohammed YH, Herrmann D, Moran I, Vennin C, Conway JR, Mélénec P, Cox TR, Wang Y, Morton JP, Welch HC, Strathdee D, Anderson KI, Phan TG, Roberts MS, Timpson P

Intravital microscopy can provide unique insights into the function of biological processes in a native context. However, physiological motion caused by peristalsis, respiration and the heartbeat can present a significant challenge, particularly for functional readouts such as fluorescence lifetime imaging (FLIM), which require longer acquisition times to obtain a quantitative readout. Here, we present and benchmark , a versatile multi-platform software tool for image-based correction of sample motion blurring in both time resolved and conventional laser scanning fluorescence microscopy data in two and three dimensions. We show that is able to resolve intravital FLIM-FRET images of intra-abdominal organs in murine models and NADH autofluorescence of human dermal tissue imaging subject to a wide range of physiological motions. Thus, can enable FLIM imaging in situations where a stable imaging platform is not always possible and rescue previously discarded quantitative imaging data.

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eLife, 7, 2050-084X, , 2018

PMID: 29985127

Rac-GTPases and Rac-GEFs in neutrophil adhesion, migration and recruitment.
Pantarelli C, Welch HCE

Rac-GTPases and their Rac-GEF activators play important roles in the recruitment and host defense functions of neutrophils. These proteins control the activation of adhesion molecules and the cytoskeletal dynamics that enable the adhesion, migration and tissue recruitment of neutrophils. They also regulate the effector functions that allow neutrophils to kill bacterial and fungal pathogens, and to clear debris. This review focusses on the roles of Rac-GTPases and Rac-GEFs in neutrophil adhesion, migration and recruitment. This article is protected by copyright. All rights reserved.

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European journal of clinical investigation, , 1365-2362, e12939, 2018

PMID: 29682742

A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts.
Nobis M, Herrmann D, Warren SC, Kadir S, Leung W, Killen M, Magenau A, Stevenson D, Lucas MC, Reischmann N, Vennin C, Conway JRW, Boulghourjian A, Zaratzian A, Law AM, Gallego-Ortega D, Ormandy CJ, Walters SN, Grey ST, Bailey J, Chtanova T, Quinn JMW, Baldock PA, Croucher PI, Schwarz JP, Mrowinska A, Zhang L, Herzog H, Masedunskas A, Hardeman EC, Gunning PW, Del Monte-Nieto G, Harvey RP, Samuel MS, Pajic M, McGhee EJ, Johnsson AE, Sansom OJ, Welch HCE, Morton JP, Strathdee D, Anderson KI, Timpson P

The small GTPase RhoA is involved in a variety of fundamental processes in normal tissue. Spatiotemporal control of RhoA is thought to govern mechanosensing, growth, and motility of cells, while its deregulation is associated with disease development. Here, we describe the generation of a RhoA-fluorescence resonance energy transfer (FRET) biosensor mouse and its utility for monitoring real-time activity of RhoA in a variety of native tissues in vivo. We assess changes in RhoA activity during mechanosensing of osteocytes within the bone and during neutrophil migration. We also demonstrate spatiotemporal order of RhoA activity within crypt cells of the small intestine and during different stages of mammary gestation. Subsequently, we reveal co-option of RhoA activity in both invasive breast and pancreatic cancers, and we assess drug targeting in these disease settings, illustrating the potential for utilizing this mouse to study RhoA activity in vivo in real time.

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Cell reports, 21, 2211-1247, 274-288, 2017

PMID: 28978480

Group Members

Latest Publications

Removing physiological motion from intravital and clinical functional imaging data.

Warren SC, Nobis M, Magenau A

eLife
7 2050-084X: (2018)

PMID: 29985127

Rac-GTPases and Rac-GEFs in neutrophil adhesion, migration and recruitment.

Pantarelli C, Welch HCE

European journal of clinical investigation
1365-2362:e12939 (2018)

PMID: 29682742

A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts.

Nobis M, Herrmann D, Warren SC

Cell reports
21 2211-1247:274-288 (2017)

PMID: 28978480

Platelets in neutrophil recruitment to sites of inflammation.

Pitchford S, Pan D, Welch HC

Current opinion in hematology
1531-7048: (2016)

PMID: 27820736

Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma.

Lissanu Deribe Y, Shi Y, Rai K

Proceedings of the National Academy of Sciences of the United States of America
1091-6490: (2016)

PMID: 26884185

Norbin Stimulates the Catalytic Activity and Plasma Membrane Localization of the Guanine-Nucleotide Exchange Factor P-Rex1.

Pan D, Barber MA, Hornigold K

The Journal of biological chemistry
1083-351X: (2016)

PMID: 26792863

Small GTPases and their guanine-nucleotide exchange factors and GTPase-activating proteins in neutrophil recruitment.

Baker MJ, Pan D, Welch HC

Current opinion in hematology
23 1531-7048:44-54 (2016)

PMID: 26619317

Regulation and Function of P-Rex Family Rac-GEFs.

Welch HC

Small GTPases
2154-1256:0 (2015)

PMID: 25961466

P-Rex and Vav Rac-GEFs in platelets control leukocyte recruitment to sites of inflammation.

Pan D, Amison RT, Riffo-Vasquez Y

Blood
1528-0020: (2014)

PMID: 25538043

A rac1-independent role for p-rex1 in melanoblasts.

Lindsay CR, Li A, Faller W

The Journal of investigative dermatology
135 1523-1747:314-8 (2015)

PMID: 25075639

P-Rex1 directly activates RhoG to regulate GPCR-driven Rac signalling and actin polarity in neutrophils.

G Damoulakis, L Gambardella, KL Rossman

Journal of cell science
127 Pt 11:2589-600 (2014)

DOI: 10.1242/jcs.153049

PMID: 24659802