Germline Stem Cell Biology
Research Group Head
The maintenance of male fertility is dependent on spermatogonial stem cells (SSCs) that self-renew and generate differentiating germ cells for production of spermatozoa. After puberty, this process continuously produces mature sperm to maintain lifelong fertility. SSC function is dependent on specific growth factors produced within the testis microenvironment plus distinct cellular factors that regulate gene expression within SSCs and modulate responses to growth factor stimulation. However, despite the importance of SSCs for male fertility, the molecular mechanisms that regulate their function and maintenance remain incompletely understood.
Importantly, SSC function and male fertility can be compromised by multiple factors including ageing or exposure to genotoxic drugs. Increased paternal age is associated with disruption of SSC activity and declining sperm quality, with an elevated risk of genetic diseases in offspring. Infertility can also occur prematurely in men as a consequence of genotoxic therapies eg; chemotherapy, for treatment of cancer. However, cellular pathways mediating the regenerative response of SSCs following germline damage and loss of SSC function with age are poorly studied.
Our research focuses on defining genetic controls and cellular pathways regulating SSC function and male fertility. We employ a range of in vivo and in vitro experimental systems allowing dissection of mammalian SSC function. Our previous work has defined essential roles for the developmental transcription factors PLZF and SALL4 in maintenance of SSC activity and the central importance of mTORC1 signalling in SSC fate regulation. In addition, our studies have characterised cellular heterogeneity within the SSC and progenitor cell pool using single cell approaches and demonstrated the dynamic nature of spermatogonial states with important clinical implications.
Current research projects are focused on understanding cellular machinery modulating the response of SSCs to stimuli from the niche, the impacts of ageing on SSC function and molecular mechanisms supporting the regenerative capacity of SSCs.
McAninch D, Mäkelä JA, La HM, Hughes JN, Lovell-Badge R, Hobbs RM, Thomas PQ (2020) SOX3 promotes generation of committed spermatogonia in postnatal mouse testes. Scientific Reports 10:6751.
La HM, Hobbs RM (2019) Mechanisms regulating mammalian spermatogenesis and fertility recovery following germ cell depletion. Cellular and Molecular Life Sciences. 76:4071-4102.
Legrand JMD, Chan AL, La HM, Rossello FJ, Änkö ML, Fuller-Pace FV, Hobbs RM (2019) DDX5 plays essential transcriptional and post-transcriptional roles in the maintenance and function of spermatogonia. Nature Communications 10: 2278.
Liao J, Ng SH, Luk AC, Suen HC, Qian Y, Lee AWT, Tu J, Fung JCL, Tang NLS, Feng B, Chan WY, Fouchet P, Hobbs RM, Lee TL (2019) Revealing cellular and molecular transitions in neonatal germ cell differentiation using single cell RNA sequencing. Development 146 (6). pii: dev174953.
La HM, Chan AL, Legrand JMD, Rossello FJ, Gangemi CG, Papa A, Cheng Q, Morand EF, Hobbs RM (2018) GILZ-dependent modulation of mTORC1 regulates spermatogonial maintenance. Development 145 (18) pii: dev165324.
La HM, Mäkelä JA, Chan AL, Rossello FJ, Nefzger CM, Legrand JMD, De Seram M, Polo JM, Hobbs RM (2018) Identification of dynamic undifferentiated cell states within the male germline. Nature Communications 9: 2819.
Sinha D, Kalimutho M, Bowles J, Chan AL, Merriner DJ, Bain AL, Simmons JL, Freire R, Lopez JA, Hobbs RM, O’Bryan MK, Khanna KK (2018) Cep55 overexpression causes male-specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of PI3K/Akt signaling. FASEB Journal 32:4984-4999.
Chan AL, La HM, Legrand JMD, Makela JA, Eichenlaub M, De Seram M, Ramialison M, Hobbs RM (2017) Germline Stem Cell Activity Is Sustained by SALL4-Dependent Silencing of Distinct Tumor Suppressor Genes. Stem Cell Reports 9: 956-971.
Hobbs RM, La HM, Makela JA, Kobayashi T, Noda T, Pandolfi PP (2015) Distinct germline progenitor subsets defined through Tsc2-mTORC1 signaling. EMBO Reports 16: 467-480.
Ngo D, Cheng Q, O’Connor AE, DeBoer KD, Lo CY, Beaulieu E, De Seram M, Hobbs RM, O’Bryan MK, Morand EF (2013) Glucocorticoid-induced leucine zipper (GILZ) regulates testicular FOXO1 activity and spermatogonial stem cell (SSC) function. PLoS One 8: e59149.