Professor Andrew Furley

Our research is focussed on the role L1CAM-like cell adhesion molecules (L1-CNTNs) in neural development and disease (Gennarini et al., 2017; Gennarini & Furley., 2017). L1-CNTNs affect neural function at all stages, including the earliest proliferation and differentiation of progenitor and stem cells (Bizzoca et al 2003; Ma et al 2008; Xenaki et al., 2011; Bizzoca et al., 2012; Ha et al., 2015), the guidance of axons (Cohen et al 1998; Law et al 2008; Dang et al 2012), through to firing of action potentials (Poliak et al 2003) and functioning of synapses (Bliss et al 2000). As a result, these molecules are widely implicated in neurological disease and cancers.

Our aim is to understand the cellular mechanisms through which L1-CNTNs affect this wide variety of processes. Our current work is focussed particularly on the role of NrCAM in regulating the Sonic Hedgehog (SHH) pathway in medulloblastoma (Sakurai et al., 2001; Xenaki et al., 2011) and in neural stem cells (Bizzoca et al., 2012), with a specific emphasis on its role in controlling the trafficking of SHH pathway components into and out of primary cilia (Basu et al., 2015).

Most recently, we have begun to use neural organoids derived from human induced pluripotent cells (iPSCs) to develop in vitro systems with which to study both L1-CNTN function and to generate hypothalamic progenitors and neurons (with Barbaric and Placzek in BMS).

The cell biology of signal modulation in neural development and cancer

In biology context is everything. We aim to understand how cellular context alters the responses of cells to intercellular signals, focussing on the role of the L1-contactin ‘adhesion’ molecules (L1-CNTNs) in neural development. We have shown L1-CNTNs to modulate signals as diverse as semaphorins and hedgehogs (HHs) by altering the intracellular trafficking of their receptors during signalling. Our work on L1-CNTN modulation of Sema signalling during the wiring of mouse spinal sensory circuits (Dang et al 2012) has converged on our studies showing F3/contactin repression of Sonic HH-stimulated proliferation of cerebellar neuron progenitors (Xenaki et al 2011) to focus on a potential role for NrCAM in the trafficking of SHH signalling pathway components in the primary cilium. We are collaborating with Cadby (Physics) to develop STORM super resolution microscopy to follow this in real time (Peedikakkal et al., 2017). Collaborations with Clifford (Newcastle) reveal NrCAM to be upregulated in SHH group medulloblastomas and loss of NrCAM in vivo affects the penetrance of neoplasia in the Ptch1 mouse medulloblastoma model (Basu et al., 2015).

Roles for NrCAM in hypothalamic stem cell behaviour and for TAG1 in autism and obesity (3) are also being investigated with Placzek (BMS), Markx (NY) and Buchner (Ohio; Buchner et al 2012) respectively, while with Whyte, Walmsley (Edinburgh) and Renshaw (IICD/Bateson) we have investigated semaphorins in neutrophil function (Plant et al., 2020).

I also have a particular interest in the use of animals in research, which relates to my masters Bioethics teaching (with Townend, Maastricht), and was the Sheffield lead in an FP7 project (ANIMPACT) aimed at evaluating the impact of Directive 2010/63/EU on animal welfare and research competitiveness in member states (Fernandes et al., 2019).