Professor Alan McNeilly

Alan McNeillyJob Title:
Principal Investigator
Honorary Professor of Reproductive Endocrinology

Contact details:
Telephone: +44(0) 131 242 6162   Email: a.mcneilly@ed.ac.uk

Research Interests

Our major aim is to determine how ovarian follicular development is controlled both from within the ovary and by the pituitary, so that at ovulation only good eggs are released leading to the birth of healthy babies. As model systems we use cell and tissue culture, transgenic mice to study the effects of gene addition or deletion, and sheep as a model mono-ovular species having very similar reproductive endocrinology and ovarian biology to women. We collaborate with clinical colleagues to examine human tissues.

We are particularly interested in the influence of the TGFß superfamily of growth factors in regulating pituitary function and ovarian follicle growth and maturation. Our previous research examined how the gonadotrophins LH and FSH, regulated follicle growth, and how feedback from the ovary regulated LH and FSH output. Within the pituitary we showed that differential secretion of LH and FSH from the bihormonal LH/FSH gonadotrope cell is achieved by different intracellular pathways for processing and packaging LH and FSH. Our studies in transgenic mice have uncovered a novel mechanism for regulating the sensitivity of the ovarian follicle for survival, ensuring maintained egg quality and increased numbers of babies. Furthermore when the gene responsible is deleted resulting in complete oocyte loss at birth the ovary remains steroidogenically active and becomes hyperplastic with age. These responses provide leads to novel factors within the oocytes that regulate the healthy maturation of the oocyte within the follicle, and how the granulosa cells of the follicle talk to the surrounding stromal tissue and prevent tumor-like growth in the ovary.

We have identified a number of single base mutations in an oocyte specific gene GDF9 that affects fertility, and rams carrying this gene are being introduced into sheep production systems. Collaborative studies are also investigating how exposure the androgens and other steroids in fetal life affect adult ovarian function as models for Polycystic Ovary Syndrome in women. Finally we are investigating the changes in the microcirculation in the ovary using contrast-enhanced ultrasound in sheep as a model for the human. New software has been developed with our collaborators in Medical Physics and will be investigated with clinical colleagues in Edinburgh to determine changes in the microcirculation in the human ovary, placenta and as a potential diagnostic for ectopic pregnancies. All these studies benefit enormously from the extensive collaborations with colleagues in the UK, Australia, Brazil, China, France, New Zealand and Spain.

Current research projects

  • Regulation of ovarian follicle growth
  • Role of microcirculation in ovarian function
  • Identification of genes regulating ovulation rate

Grants

1/4/20011-31/1/2013 MRC Unit grant
Gene targeting and control of ovarian function £180,000

2006-2011 MRC Unit grant G7 002.00007.01
Gene targeting and control of ovarian function £1.8m

2009-2012 MRC project grant G0800896
Development of contrast enhanced ultrasonography using the sheep ovarian model of microvascular regulation. Investigators V Sboros, C Fox, WC Duncan, HM Fraser, AS McNeilly £840,954

2006-2010 MRC project grant
Polycystic Ovarian Syndrome: modeling development, phenotype and progression using a developmental paradigm. Investigators WC Duncan, AS McNeilly £281,187

2010-2013 MRC project grant G080
Polycystic Ovarian Syndrome: manipulation of hormonal, metabolic and ovarian phenotypes using a developmental model Investigators WC Duncan, M Rae, AS McNeilly £790,411

2010-32013 BBSRC project grant BB/H014098/1 The FecB gene may increase prolificacy by modulating multiple local regulatory pathways. Investigators BK Campbell (Nottingham), DT Baird AS McNeilly £659,589

2010-32012 Royal Society International Joint Project grant JP090730

Function of GDF9 in bitch reproduction as a target for immunosterilization. AS McNeilly and Carlos Souza (Embrapa, Bage, Brazil) £11920

Key publications

  • Berlinguer F, Gonzalez-Bulnes A, Spezzigu A, Contreras-Solis I, Succu S, McNeilly AS, Naitana S, Leoni GG (2012). Effect of aging on follicular function may be relieved by exogenous gonadotropin treatment in a sheep model. Reproduction (2012) 144 245–255. DOI: 10.1530/REP-12-0030
  • Childs A, McNeilly AS (2012). Commentary: Epithelial-to-mesenchymal transition in granulosa cells: a key to activation of follicle growth? Biology of Reproduction doi:10.1095/biolreprod.112.100156.
  • Eghbal S, Nicol L, McNeilly AS et al (2012). Presence of SNPs in GDF9 mRNA of Iranian Afshari sheep. International Journal of Fertility and Sterility 5: 225-230.
  • Hogg K, Young J, Oliver EM, Souza C, McNeilly AS, Duncan WC (2012). Enhanced thecal androgen production is prenatally programmed  in an ovine model of polycystic ovary syndrome. Endocrinology 153: 450-461. PMID: 22087026
  • Semprini S, McNamara AV, Raheela A, Featherstone K, Harper CV, McNeilly JR, Patist A, Rossi, AG, Dransfiled I, McNeilly AS, Davis JRE, White M, Mullins JJ (2012) Pritonitis activates transcription of the human prolactin locus in a humanized transgenic rat model. Endocrinology 153: 2724-2734. doi: 10.1210/en.2011-1926.
  • Tartarin P, Guibert E, Toure A, Leclerc J, Briere S, Dacheux JL, Delaleu B, McNeilly JR, McNeilly AS, Dupont J, Brillard JP, Foretz M, Viollet B, Froment P (2012) Inactivation of AMPK alpha1 induces asthenozoospermia and alters spermatozoa morphology. Endocrinology 153: 3468-3481. doi: 10.1210/en.2011-1911.
  • Tyndall V, Broyde M, Sharpe RM, Welsh M, Drake AJ, McNeilly AS (2012). Effect of androgen treatment during fetal and/or neonatal life on ovarian function and metabolic factors in rats: a potential model of polycystic ovary syndrome. Reproduction 143 21-33. PMID: 22016380; DOI: 10.1530/REP-11-0239.
  • Young JM, Henderson S, Souza C, Ludlow H, Groome N, McNeilly AS (2012) Activin B is produced early in antral follicular development and suppresses thecal androgen production. Reproduction 143: 1-15. doi:10.1530/REP-11-0327.
  • Tyndall V, Broyde M, Sharpe RM, Welsh M, Drake AJ, McNeilly AS (2012). Effect of androgen treatment during fetal and/or neonatal life on ovarian function and metabolic factors in rats: a potential model of polycystic ovary syndrome. Reproduction 143 21-33. PMID: 22016380
  • Hogg K, Young J, Oliver EM, Souza C, McNeilly AS, Duncan WC (2012). Enhanced thecal androgen production is prenatally programmed  in an ovine model of polycystic ovary syndrome. Endocrinology 153: 450461. PMID: 22087026
  • Young JM, McNeilly AS (2011) Inhibin removes the inhibitory effects of activin on steroid enzyme expression and androgen production by normal ovarian thecal cells. Journal of Molecular Endocrinology 48: 1-13. PMID: 22082494
  • McNeilly JR, Watson E, Brown Y, Murray AA, Spears N, McNeilly AS (2011) Decreased oocyte DAZL expression results in increased litter size by modulating FSH-induced follicle growth. Biology of Reproduction biolreprod.110.086264
  • McNeilly AS (2011). Diagnostic applications for inhibin and activin. Molecular and Cellular Endocrinology 10.1016/j.mce.2011.06.017 PMID: 21741437
  • Hogg K, McNeilly AS, Duncan WC (2011) Prenatal androgen exposure leads to alterations in gene and protein expression in the ovine fetal ovary. Endocrinology 152: 2048-2059. (doi:10.1210/en.2010-1219). PMID: 21325046
  • Hogg K, Wood C, McNeilly AS, Duncan WC (2011) The in utero programming effect of increased maternal androgens and a direct fetal intervention on liver and metabolic function in adult sheep. PLoS One 6 e24877. PMID: 21935484
  • Sboros V, Averkiou M, Thomas DH, Silva N, Lampaskis M, Strouthos K, Docherty J, McNeilly AS (2011) Imaging of the ovine corpus luteum microcirculation with contrast ultrasound. Ultrasound in Medicine and Biology 37: 59-68.
  • Young J, McNeilly AS (2010) Theca – the forgotten cell of the ovarian follicle. Reproduction 140: 489-504.
  • Hogg K, Etherington SL, Young J, McNeilly AS, Duncan C (2010) Inhibitor of differentiation (Id) genes are expressed in the steroidogenic cells of the ovine ovary and are differentially regulated by members of the Transforming Growth Factor (TGF)-ß family. Endocrinology 151: 1247-1256.
  • Nicol L, Bishop, S, Rhind, SM, Bendixen, C, Holm LE., McNeilly AS (2009). Homozygosity for a single base-pair mutation in the oocyte-specific GDF9 gene results in sterility in homozygous Thoka sheep. Reproduction 138: 921-933.
  • Onions VJ, Webb R, McNeilly AS, Campbell BK (2009) Ovarian endocrine profile and long-term vascular patency following heterotopic autotransplantation of cryopreserved whole ovine ovaries. Human Reproduction 24: 2845-2855.
  • Nicol L, Faure M-O, McNeilly JR, Fontaine J, Taragnat C, McNeilly AS (2008) BMP-4 interacts with activin and GnRH to modulate gonadotropin secretion in LßT2 gonadotropes. Journal of Endocrinology 196: 497-507.
  • Pope C, McNeilly JR, Coutts S, Millar M, Anderson RA, McNeilly AS (2006) Gonadotrope and thyrotrope development in the human and mouse fetal anterior pituitary gland. Developmental Biology 297: 172-181.

Staff/group members

Julie Hastings, Sarah Henderson, Linda Nicol, Kasia Miedzinska and Judy McNeilly

PhD students:
Vicky Tyndall graduated 2011; Kirsten Hogg graduated 2011 (Lead supervisor Colin Duncan); Joao Pedro Sousa Martins (Lead supervisor Nikki Gray); Sadanand Sontakre (Lead supervisor Xavier Donadeau).

Principal collaborators

WC Duncan and M Rae (PCOS studies), BK Campbell and DT Baird (ALK6 mutation ovarian effects), V Sboros (Contrast-enhanced ultrasound), C Sousa and S Rhind (GDF9 and fertility), A Loudon, D Burt, JRE Davis, M White, R Fowkes and J Mullins (Transcriptional regulation of pituitary and seasonal effects), C Taragnat and Cui Sheng (Growth factors and pituitary regulation), J Pitman and KP McNatty (Ovarian tumorogenesis).

Responsibilities

Chair, Society for Endocrinology Science Committee 2008-date; Member, Society for Study of Reproduction Meetings Committee 2011-date; Member, Society for Study of Reproduction Heritage Committee 2011-date; Member Faculty of 1000 2009-date.

Honours

Fellow of the Royal Society of Edinburgh 1995; Dale Medalist, Society for Endocrinology, 2008; Marshall Medalist, Society for Reproduction and Fertility 2010; Fellow of the Society for Biology 2010.