Biology subjects

Delgado, K. C.

Publications and source records attributed to Delgado, K. C..

3 recordsLinked to original sources

bioRxiv2025

Visual input drives diverse ER calcium signals in neurons in vivo

The endoplasmic reticulum (ER) has long been thought to shape calcium signals in neurons, but stimulus-driven ER calcium fluctuations have not been directly measured in vivo. To measure neuronal ER calcium signals in vivo, we paired visual stimulus presentation with two photon imaging of ER and cytosolic calcium reporters in four different cell types in the Drosophila visual system. We found that visual input elicits diverse ER calcium signals, with the ER acting as a calcium sink or source depending on the cell type, subcellular compartment (dendrite versus axon), and type of visual stimulus. ER calcium signals were not simply a reflection of cytosolic signals, indicating that the ER, rather than acting as a passive calcium buffer, actively processes calcium signals in neurons in a context-specific fashion. Thus, ER-based signal processing may contribute to functional diversity across neuronal cell types, thereby enhancing the computational capacity of neural circuits.

neuroscience↗

bioRxiv2021

c-Kit mediates cutaneous sensory axon innervation and multi-kinase inhibitor-induced neurotoxicity

Peripheral somatosensory neurons innervate the skin and sense the environment. Loss of skin innervation, often caused by the "dying back" of distal somatosensory axons, is a common side effect of drug-induced peripheral neuropathies (DIPNs) and results in pain and sensory dysfunction. Targeted cancer therapies frequently employ multi-kinase inhibitor (MKI) drugs that each block multiple receptor tyrosine kinases. Many MKIs produce DIPNs but the molecular targets and cellular mechanisms underlying these are unknown. We performed live-imaging of cutaneous somatosensory axons in larval zebrafish during treatment with several MKIs known to induce DIPNs, and observed axonal retraction consistent with a dying back pathology. These results were replicated in mouse somatosensory neurons. Genetic knockout of potential MKI targets identified c-Kit receptor as a regulator of sensory axon innervation and a major target of these MKIs mediating loss of axonal density. In both fish and mammals, Kit receptor is expressed in cutaneous somatosensory neurons and its ligand, Kitlg, is expressed in the skin. Mosaic misexpression of Kitlg in the skin induced dramatic increases in local sensory axon density, suggesting an important role for Kit signaling in cutaneous axon growth and maintenance. Immunostaining and structure-function analysis revealed Src, a downstream Kit target, mediates Kits role in cutaneous axon innervation and MKI neurotoxicity. Our data shows that the Kit-Src signaling pathway has a major role in cutaneous sensory axon innervation and is a potential therapeutic target to address DIPNs caused by MKIs and other compounds.

neuroscience↗

bioRxiv2019

Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination

The form of Charcot-Marie-Tooth type 4B (CMT4B) disease caused by mutations in myotubularin-related 5 (MTMR5; also called SET Binding Factor 1; SBF1) shows a spectrum of axonal and demyelinating nerve phenotypes. This contrasts with the CMT4B subtypes caused by MTMR2 or MTMR13 (SBF2) mutations, which are characterized by myelin outfoldings and classic demyelination. Thus, it is unclear whether MTMR5 plays an analogous or distinct role from that of its homolog, MTMR13, in the peripheral nervous system (PNS). MTMR5 and MTMR13 are pseudophosphatases predicted to regulate endosomal trafficking by activating Rab GTPases and binding to the phosphoinositide 3-phosphatase MTMR2. In the mouse PNS, Mtmr2 was required to maintain wild type levels of Mtmr5 and Mtmr13, suggesting that these factors function in discrete protein complexes. Genetic elimination of both Mtmr5 and Mtmr13 in mice led to perinatal lethality, indicating that the two proteins have partially redundant functions during embryogenesis. Loss of Mtmr5 in mice did not cause CMT4B-like myelin outfoldings. However, adult Mtmr5-/- mouse nerves contained fewer myelinated axons than control nerves, likely as a result of axon radial sorting defects. Mtmr5 levels were highest during axon radial sorting, whereas Mtmr13 levels rose as myelin formed, and remained high through adulthood. Our findings suggest that Mtmr5 and Mtmr13 ensure proper axon radial sorting and Schwann cell myelination, respectively, perhaps through their direct interactions with Mtmr2. This study enhances our understanding of the non-redundant roles of the endosomal regulators MTMR5 and MTMR13 during normal peripheral nerve development and disease.

neuroscience↗