Biology subjects

Schoofs, A.

Publications and source records attributed to Schoofs, A..

6 recordsLinked to original sources

bioRxiv2026

A druggable ATP13A3-antizyme switch controls adaptive polyamine uptake in cancer

Cellular polyamine depletion is a promising anticancer strategy, but compensatory polyamine uptake limits efficacy when synthesis is blocked by DFMO (difluoromethylornithine), a clinically approved inhibitor of ornithine decarboxylase. The transporter and feedback mechanism driving this adaptive response have remained unclear. Despite their similar biochemical properties, we identify ATP13A3, rather than ATP13A2, as the principal DFMO-responsive polyamine importer, suggesting that these isoforms regulate distinct polyamine fluxes. Mechanistically, the polyamine sensor antizyme not only restrains polyamine biosynthesis but also selectively inhibits ATP13A3-mediated uptake, a brake that is relieved upon DFMO treatment. This regulatory circuit exposes distinct polyamine-acquisition states across cancers, defining synthesis- and/or uptake-biased subtypes that can shift during disease progression. Melanoma metastasis and vemurafenib resistance evolve toward increased ATP13A3-dependent uptake. The polyamine uptake branch controlled by ATP13A3-antizyme regulation can be pharmacologically blocked by AMXT 1501, which directly inhibits ATP13A3. Together, our findings explain DFMO adaptation through ATP13A3-antizyme control and establish ATP13A3 as a targetable node for polyamine depletion strategies in multiple cancers, supporting ongoing clinical evaluation of combined DFMO/AMXT 1501 therapy.

cell biology↗

bioRxiv2026

An aorta to insulin producing cell sensor for internal state in Drosophila

The cellular circuits through which the internal state of an organism is sensed and relayed to the brain, and through which they bring about appropriate physiological and behavioral responses, remain largely unelucidated. Using whole-animal electron microscopy reconstruction of a Drosophila larva, we previously identified an Aorta sensory organ whose somata lie on the periphery of the brain, with dendritic arborizations in the wall of the anterior aorta, and whose axons project to the protocerebrum and synapse onto the insulin-producing cells (IPCs). Here we characterize the full anatomy and connectivity of this sensory organ. We show that the aorta sensory neurons make their strongest direct synaptic contacts onto IPCs and the neurosecretory cells producing Dromyosuppressin (DMS), with only weaker direct contacts to diuretic hormone 44 (DH44). They also make direct contacts to the enteric serotonergic neurons modulating swallowing (Se0ens), and to two single mushroom body neurons, DAN-j1 and MBON-d3, of the learning and memory center of Drosophila. Calcium imaging shows that the neurons are activated by fructose, and optogenetic manipulation reveals that their activity influences peptide content in IPCs, DH44 and DMS cells. Polysynaptic paths to the brain run through two morphologically distinct interneuron families. One, formed by the Hugin protocerebral neurons, targets the neuroendocrine system and is associated with bitter taste and pathogen induced feeding suppression. The other, formed by the BAmas projection neurons, targets dopaminergic input neurons and output neurons of the mushroom body. The Aorta sensory pathway therefore couples internal hemolymph state to two parallel central systems -- endocrine state control and mushroom body-associated value updating -- and provides a candidate substrate for a metabolic memory through which post-ingestive state is fed back into future feeding choice.

neuroscience↗

bioRxiv2023

Morphology and ultrastructure of external sense organsof Drosophila larvae

Sensory perception is the ability through which an organism is able to process sensory stimuli from the environment. This stimulus is transmitted from the peripheral sensory organs to the central nervous system, where it is interpreted. Drosophila melanogaster larvae possess peripheral sense organs on their head, thoracic, and abdominal segments. These are specialized to receive diverse environmental information, such as olfactory, gustatory, temperature or mechanosensory signals. In this work, we complete the description of the morphology of external larval sensilla and provide a comprehensive map of the ultrastructure of the different types of sensilla that comprise them. This was achieved by 3D electron microscopic analysis of partial and whole body volumes, which contain high-resolution and complete three-dimensional data of the anatomy of the sensilla and adjacent ganglia. Our analysis revealed three main types of sensilla on thoracic and abdominal segments: the papilla sensillum, the hair sensillum and the knob sensillum. They occur solitary or organized in compound sensilla such as the thoracic keilins organ or the terminal sensory cones. We present a spatial map defining these sensilla by their position on thoracic and abdominal segments. Further, we identify and name the sensilla at the larval head and the last fused abdominal segments. We show that mechanosensation dominates in the larval peripheral nervous system, as most sensilla have corresponding structural properties. The result of this work, the construction of a complete structural and neuronal map of the external larval sensilla, provides the basis for following molecular and functional studies to understand which sensory strategies the Drosophila larva employs to orient itself in its natural environment.

neuroscience↗

bioRxiv2023

Serotonergic reinforcement of a complete swallowing circuit

How the body interacts with the brain to perform vital life functions such as feeding is one of the fundamental questions in physiology and neuroscience. Here, we use a whole-animal scanning transmission electron microscopy dataset of Drosophila to map out the neuronal circuits that connect the entire enteric nervous system to the brain via the insect vagus nerve at synaptic resolution. This revealed a periphery-brain feedback loop in which Piezo-expressing mechanosensory neurons sense food intake and convey that information onto serotonergic neurons within the brain. These serotonergic neurons integrate the interoceptive information with external and central inputs, and in turn stabilize rhythmic activity of serotonin receptor 7 expressing peripheral motor neurons that drive swallowing. Strikingly, the very same motor neurons also share an efference copy of their activity with the aforementioned mechanosensory neurons, thereby closing the motor-sensory-modulatory loop. Our analysis elucidates an elemental, albeit surprisingly complex reinforcement circuit in which rhythmic motor patterns are stabilized through afferent signaling to central serotonergic neurons upon completion of a rewarding action. The circuit motif is constructed to allow the distinction between self-generated action and those in response to the environment.

neuroscience↗

bioRxiv2020

Unveiling the sensory and interneuronal pathways of the neuroendocrine system in Drosophila

Neuroendocrine systems in animals maintain organismal homeostasis and regulate stress response. Although a great deal of work has been done on the neuropeptides and hormones that are released and act on target organs in the periphery, the synaptic inputs onto these neuroendocrine outputs in the brain are less well understood. Here, we use the transmission electron microscopy reconstruction of a whole central nervous system in the Drosophila larva to elucidate the sensory pathways and the interneurons that provide synaptic input to the neurosecretory cells projecting to the endocrine organs. Predicted by network modeling, we also identify a new carbon dioxide responsive network that acts on a specific set of neurosecretory cells and which include those expressing Corazonin (Crz) and Diuretic hormone 44 (DH44) neuropeptides. Our analysis reveals a neuronal network architecture for combinatorial action based on sensory and interneuronal pathways that converge onto distinct combinations of neuroendocrine outputs.

neuroscience↗

bioRxiv2018

The Feeding Connectome: Convergence of Monosynaptic and Polysynaptic Sensory Paths onto Common Motor Outputs

Little is known about the organization of central circuits by which external and internal sensory inputs act on motor outputs to regulate fundamental behaviors such as feeding. We reconstructed, from a whole CNS EM volume, the synaptic map of input and output neurons that underlie food intake behavior of Drosophila larvae. The input neurons originate from enteric, pharyngeal and external sensory organs and converge onto seven distinct sensory synaptic compartments within the CNS, as defined by distribution patterns of their presynaptic sites. The output neurons consist of pharyngeal motor neurons, serotonergic modulatory neurons, and neuroendocrine neurons that target the ring gland, a key endocrine organ. Monosynaptic connections from a set of sensory synaptic compartments cover the motor and endocrine targets in overlapping domains. Polysynaptic routes can be superimposed on top of the monosynaptic connections, resulting in divergent sensory paths that converge on common motor outputs. A completely different set of sensory compartments is connected to the mushroom body calyx of the memory circuits. Our results illustrate a circuit architecture in which monosynaptic and multisynaptic connections from sensory inputs traverse onto output neurons via a series of converging paths.

neuroscience↗