Title
Professor and Vice Chair
Ph.D.
National Institute for Medical Research/King’s College London, U.K.
Post Doc Training
Stanford University and the University of California, San Francisco
Major Interests
Control of cell fate–
Deficiencies of pituitary-derived hormones, due to genetic causes, head injury, under or over-nutrition, or as a consequence of pituitary cancer treatment cause severe morbidity. The anterior pituitary (AP) gland displays considerable cellular plasticity that functions to meet the fluctuating hormonal and gender-specific needs of the body. However, the molecular processes underpinning this regulated cellular plasticity in the AP have not been fully elucidated. Proposed processes involve regulation of resident Sox2-expressing stem cell populations and the transdifferentiation of hormone producing cells via a cell phenotypic switch without cell division.
The manipulation of endogenous pituitary cell plasticity may present a therapeutic strategy to treat pituitary deficiencies. Current strategies to treat pituitary deficiencies use hormone replacement which do not fully mimic physiological pulsatile secretion regimes and so regeneration of missing endocrine cell lineages would be a significant clinical improvement over current treatment options.
Our ongoing studies employ single cell RNA sequencing and proteogenomics to address the molecular mechanisms underlying pituitary plasticity and to understand the dysregulation of pituitary plasticity under conditions of organismal stress, such as occurs in obesity or during menopause.
Post-transcriptional control of gene expression–
MicroRNAs (miRNAs) regulate gene expression at multiple levels, including post-transcriptional control. Their role in gonadotrope function has been revealed through Dicer deletion mutant mice that show suppressed gonadotropin synthesis and secretion along with infertility in both males and females. We have also reported that leptin can modulate miRNA expression in somatotropes, suggesting a broad role for miRNA-dependent regulation in control of pituitary function. Several RNA binding proteins have been implicated in the control of pituitary function. The Gnrhr mRNA is an ELAVL1 target in the gonadotrope-like LbT2 cell line and knockdown of ELAVL1 reduces GnRHR protein levels and LH secretion in response to GnRH. We discovered that the RNA-regulatory protein Musashi (MSI), also mediates the post-transcriptional control of gonadotrope gene expression. MSI was originally shown to function to repress target mRNAs that promote differentiation and thus acts to maintain stem cell self-renewal. We were the first to demonstrate that MSI can also direct target mRNA translational activation in a cell context-dependent manner. Unexpectedly, MSI is highly expressed in mature hormone-producing cell lineages of the AP. MSI RIPseq identified 1184 pituitary mRNAs that interact specifically with MSI, suggesting a broad role for MSI action in modulating hormone secretion and lineage specification. While MSI exerts translational repression on the Pou1f1, Gnrhr, Prl, Tshb and Fshb mRNAs, our new data demonstrate that MSI can activate a subset of its pituitary mRNA targets, including the Prop1 and Gata2 mRNAs. However, the mechanism by which MSI selectively represses or activates distinct mRNA targets is not known.
Our ongoing studies employ mRNA capture and mass spectrometry to identify the full range of proteins that function within MSI activator messenger ribonucleoprotein (mRNP) or repressor mRNP complexes.
Stem cells and cancer stem cells–
The Musashi (MSI) protein family are critical regulators of physiological stem cell fate and have been implicated pathologically in a range of diseases including cancer, neurodegeneration and fetal microcephaly induced by Zika viral infection. Manipulation of MSI function is a critical therapeutic target for both treatment of disease and promoting stem-cell directed tissue regeneration.
Our recent work has revealed a role for MSI proteins in differentiated hormone-producing cell lineages in the anterior pituitary and have suggested MSI may contribute to pituitary plasticity.
Our ongoing studies employ 3D pituitary organoid cultures as well as tumor organoids as model systems to selectively manipulate MSI isoform-specific expression and/or activity to promote target tissue regeneration or attenuate cancer stem cell functionality.
Research Interests
Research-
Dr. MacNicol has over 25 years’ experience studying the mechanisms of signal transduction and cell cycle control in both mammalian and vertebrate model organisms. He also has extensive expertise in elucidating the mechanisms governing regulated mRNA translation. Indeed, working with his colleagues he has identified novel 3′ cis-regulatory elements that control temporal mRNA translational activation during Xenopus oocyte maturation, determined a “regulatory code” by which these elements functionally integrate when present in the same 3′-UTR, identified specific trans-regulatory factors that directly control these elements, and characterized the cellular signal transduction pathways that in turn regulate these trans factors and target mRNA translation in a context-dependent manner. Given his long-standing interest in cell fate determination, Dr. MacNicol has established productive collaborations with Dr. Gwen Childs, Dr. Melanie MacNicol and Dr. Angela Odle in the department to characterize the post-transcriptional control of pituitary function (17 co-author papers). Together, they have discovered that differentiated, hormone-producing cells of the anterior pituitary (AP) express high levels of immature, progenitor cell markers including the stem cell mRNA translational regulator, Musashi.Using novel mouse models, this collaborative team seek to further characterize the role and regulation of Musashi function in pituitary cell plasticity, as well as using unbiased approaches to examine regulated mRNA translation in general during pituitary stem/progenitor cell differentiation. In a complementary set of experiments, they have sought to understand the regulatory components of Musashi mRNA ribonucleoprotein complexes that differentially exert repression or activation of translation on target mRNA using Xenopus and murine model systems. Dr. MacNicol’s group employs a variety of experimental approaches including molecular biology, biochemistry, microinjection, mass spectrometry, next generation sequencing, bioinformatics of complex datasets, mammalian cell culture, 3D organoid culture, human iPSCs and morphological studies.
Mentoring-
Dr. MacNicol joined the faculty at the University of Chicago in 1994 and subsequently UAMS in 2001. Throughout his career he has placed a significant emphasis on mentoring. Dr. MacNicol has directly overseen research training for five high school students, 4 undergraduate students, 5 medical student summer rotations, 24 predoctoral rotation students, three M.D./Ph.D. students, nine postdoctoral fellows, and five junior faculty members. Nine of the PhD students have graduated, completing their PhD in an average of 4.9 years-to-degree and have successfully published their work during their tenure with the group (average 3.7 total publications and 1.1 first-author publications). They have gone on to careers in health care policy, academic research, and one returned to medical school. Two postdoctoral fellows were promoted to Instructor rank and have positions at UAMS and ACRI. Of the other seven postdoctoral fellows, two are senior fellows at academic research institutions, two are staff scientists at medical institutions, one is a tenure-track Assistant Professor, one is a tenured Associate Professor and one is Director of Bioinformatics in a start-up Biotech company in the U.K. Dr. MacNicol has been actively engaged in graduate student recruiting, admissions, and matriculation throughout his career, serving a 5-year term as chair of the Graduate Student Admissions for the Committee on Developmental Biology (University of Chicago) and 5-year term on the Graduate Student Advisory Committee for the Department of Neurobiology & Developmental Sciences (UAMS).He has also participated in the “Chairs Academy” workshops at UAMS focused on being an effective team leader, conducting “Crucial Conversations”, recognizing and combating “Implicit Bias” in hiring, retention, and promotions as well as completing the Optimizing the Practice of Mentoring online course offered by the University of Minnesota Clinical and Translational Science Institute/National Research Mentoring Network. He serves as a faculty mentor on two COBREs and the Arkansas INBRE.
Service-
Dr. MacNicol has served as Vice Chair of the department since 2019. He is a member of the departmental faculty development committee which is charged with evaluating and mentoring junior faculty (Instructors, Assistant and Associate Professors) as they progress towards promotion in their respective non-tenure or tenure-track positions. Dr. MacNicol also serves on the Internal Advisory Committee to the College of Medicine Office of Research, the UAMS Space committee and the UAMS Winthrop Rockefeller Distinguished Lectureship Committee. He has extensive teaching experience and currently lectures in both the Cell Biology and Gene Expression required UAMS GPIBS core courses. He currently serves on the editorial board of several journals including Molecular Reproduction and Development, as well as Biomolecules. He has served as an ad hoc grant reviewer for the NIH, Swiss National Science Foundation, Welcome Trust U.K., ACS, NSF, Qatar National Research Foundation and the UK Research and Innovation, Biotechnology and Biological Sciences Research Council.
Link to Dr. MacNicol’s PubMed publications
Office
Slot 814