Shane Herbert

Shane is a Principal Investigator and Senior Fellow in the Division of Developmental Biology and Medicine within the Faculty of Biology, Medicine and Health. Shane studied for his PhD at the University of Leeds in 2006 and was then awarded a Wellcome Trust Sir Henry Wellcome Fellowship in 2007 to support postdoctoral work in the laboratory of Didier Stainier at the University of California, San Francisco (UCSF). In 2011, Shane was awarded a Wellcome Trust Research Career Development Fellowship and moved to the University of Manchester to establish his own laboratory. More recently, in 2020 Shane became a Wellcome Trust Senior Research Fellow.

Deciphering instructive cues encoded in cell shape

Research in my lab addresses the fundamental question of how complex tissues arise by the process of ‘morphogenesis’ - whereby progenitor cell populations elegantly reorganise, pattern and differentiate to form distinct organs and tissues. Tissue morphogenesis is associated with dramatic changes in cell shape that define final tissue form. Yet, far from simply sculpting tissue architecture, our research reveals that these cell shape dynamics also encode critical instructive cues that direct key morphogenetic events underpinning tissue-building. As such, our work aims to define the precise role and regulation of morphogenetic cues encoded in cell shape, as well as utilise this information to predictably direct tissue formation.

To this end, we exploit the vertebrate vasculature as a key morphogenetic model to define critical cues encoded in cell shape. Blood vessel formation (or angiogenesis) is a paradigm model for study of the core mechanisms underpinning morphogenesis, including broadly conserved morphogenetic events such as collective cell migration, asymmetric cell division, competitive cell fate decisions, branching morphogenesis, tissue patterning and tubulogenesis. Moreover, dysregulation of angiogenesis underpins numerous pathological processes, including tumour growth and metastasis, retinopathy and blindness, arthritis, limb ischemia and atherosclerosis. Hence, not only do studies of angiogenesis shed light on the fundamental principles of tissue-building, but novel insights also have clear therapeutic potential.

To explore how cell shape cues direct fundamental decision-making processes driving tissue formation, we adopt a highly interdisciplinary multiscale approach integrating: (1) in vivo and in vitro live-cell imaging in the zebrafish model system and human primary cells, (2) optogenetics, signalling reporters and other genetic transgenic tools, (3) in vitro micropatterning and manipulations of cell shape, (4) ‘Omics’ techniques, (5) CRIPSR gene editing, and (6) computational modelling.

Exploiting these approaches, in recent years we’ve revealed unexpected roles for cell shape dynamics in directing asymmetric cell divisions (Lovegrove et. al., 2025. Science; Costa et. al., 2016. Nat. Cell Biol.), organelle positioning (Bradbury et. al. 2025. bioRxiv), tissue guidance (Costa et. al. 2020. EMBO J.), and competitive cell fate decisions (Zakirov et. al. 2021. Philos. Trans. R. Soc. Lond. B). Considering that cell shape change is an inherent feature of almost all forming tissues, mechanisms we uncover are likely widely conserved and of broad therapeutic relevance in diverse tissue contexts.

Interphase cell shape defines the mode, symmetry and outcome of mitosis:

Angiogenesis is coordinated by the collective migration of specialised leading “tip” and trailing “stalk” endothelial cells. Exploiting in vivo live single-cell imaging in the zebrafish model, my lab previously demonstrated that these tip and stalk cells exhibit very distinct motile behaviours and cell shape dynamics. Moreover, using an interdisciplinary approach integrating in silico computational modelling studies, we demonstrated that dividing tip cells undergo asymmetric divisions (Costa et. al., 2016. Nat. Cell Biol.). These asymmetric divisions generate daughters of distinct size and tip-stalk identities, effectively self-generating the tip-stalk hierarchy that drives angiogenesis.

More recently, we demonstrated that a fundamental trigger for these asymmetric divisions is the shape of cells in interphase (Lovegrove et. al., 2025. Science). Most cells are thought to adopt a spherical geometry in division, a process termed mitotic rounding. Indeed, endothelial cells in 2D culture exhibit classic mitotic rounding. In contrast, we find that endothelial cells and other cell types in vivo can switch to a novel “isomorphic” mode of division, which uniquely preserves pre-mitotic morphology throughout mitosis. We further identify that distinct shifts in interphase morphology act as conserved instructive cues triggering this switch to isomorphic division. Moreover, in isomorphic divisions, we find that maintenance of interphase cell morphology throughout mitosis ultimately enables cell shape to act as a geometric code defining mitotic symmetry, identity determinant partitioning, and daughter state. Thus, morphogenetic shape change both sculpts tissue form and generates the cellular heterogeneity driving tissue assembly.

mRNA localisation as a key determinant of cell shape remodelling and sensing: 

The polarised targeting of diverse mRNAs to the front of motile cells is a hallmark of cell migration, yet, precise functional roles for such targeting of mRNAs has long remained unknown. Likewise, their relevance to modulation of tissue dynamics in vivo is unclear. Using cell fractionation to isolate motile cell protrusions and RNAseq we previously defined distinct clusters of mRNAs that have unique spatial distributions in migrating endothelial cells, both in vitro and in vivo. Moreover, using single-molecule analysis, endogenous gene-edited mRNAs and zebrafish in vivo live-cell imaging, my lab previously demonstrated that such compartmentalisation RAB13 mRNA uniquely acts to promote local filopodia extension. Moreover, this local cell shape remodelling ultimately acts as a molecular compass that orients motile cell polarity and spatially direct tissue movement (Costa et. al., 2020. EMBO J).

More recently, we’ve demonstrated that another one of these targeted mRNAs directs the cell-size-scaling of mitochondria distribution and function (Bradbury et. al., 2025. bioRxiv). We find that mRNA encoding TRAK2, a key determinant of mitochondria retrograde transport, is targeted to distal sites of cell protrusions in a cell-size-dependent manner. This cell-size-scaled mRNA polarisation in turn scales mitochondria distribution by defining the precise site of TRAK2-MIRO1 retrograde transport complex assembly. As a result, excision of a 29bp 3’UTR motif that underpins this cell-size-scaling eradicates size-scaling of mitochondria positioning, triggering distal accumulation of mitochondria and progressive hypermotility as cells increase size. As such, we find an RNA-driven mechanistic basis for the cell-size-scaling of organelle distribution and function that is critical to homeostatic control of motile cell behaviour (Bradbury et. al., 2025. bioRxiv).

- Shane Herbert (Principal Investigator and Senior Fellow)

- Georgia Hulmes (Wellcome Trust Postdoctoral Fellow)

- George Charalambous (Wellcome Trust Postdoctoral Fellow)

- Brendan Capey (Wellcome Trust Postdoctoral Fellow)

- Mujtaba Ansari (BBSRC PhD Student)

- Wednesday Tarhan-King (BBSRC PhD student)