Biology subjects

Florez-Paz, D. M.

Publications and source records attributed to Florez-Paz, D. M..

3 recordsLinked to original sources

bioRxiv2023

C3 and CD47 dependent mechanisms in the refinement of sensory-motor circuits during spinal cord development

Overground movement in mammals requires the assembly and refinement of sensory-motor circuits. Within the spinal cord, sensory neurons, interneurons and motor neurons form intricate neuronal circuits to ensure proper motor control. In the developing brain, supernumerary synapses are initially formed and subsequently pruned making way for the emergence of mature circuits. However, whether this occurs within spinal sensory-motor circuits, it has not been firmly established. Moreover, it is also unknown if a combination of distinct molecules are required to refine spinal cord neuronal circuits. Here, we demonstrate the presence of supernumerary synapses which form inappropriate contacts, resulting in miswired immature spinal neuronal circuits. We determined that inappropriate synapses are of proprioceptive sensory origin and are functional, leading to impaired motor behavior. Using mouse genetics, viral-mediated neuronal map strategies, electrophysiology, and behavioral assessments, we demonstrate that two molecularly distinct mechanisms are responsible for the refinement of spinal circuits. First, we identify C3 as a major contributing factor through classical complement activation. Second, a CD47-dependent mechanism, operating in parallel to classical complement, causing elimination of inappropriate synapses. This finding underlies an unexpected function for CD47 within the spinal cord, in striking contrast to its function in the brain. Our study demonstrates that during early development, the natural course of elimination of inappropriately-generated synapses utilizes a dual fail-safe system to ensure the emergence of normal spinal reflexes and proper behavior in mice.

neuroscience↗

bioRxiv2022

Perinatal correlated retinal activity is required for the wiring of visual axons in non-image forming nuclei

The development of the visual system is an intricate and multi-step process involving the precise connection of retinal ganglion cell (RGC) axon terminals with their corresponding neurons in the visual nuclei of the brain. Upon reaching primary image-forming nuclei (IFN), such as the superior colliculus and the lateral geniculate nucleus, RGC axons undergo extensive arborization that refines over the first few postnatal weeks. The molecular mechanisms driving this activity-dependent remodeling process, which is influenced by spontaneous activity in the developing retina, are still not well understood. In this study, by manipulating the activity of RGCs in mice and analyzing their transcriptomic profiles before eye opening, we have identified gene programs involved in activity-dependent refinement. Furthermore, while RGC axons also target non-image forming nuclei (NIFN), the impact of spontaneous retinal activity on the development of these accessory nuclei, has not yet been elucidated. The analysis of visual terminals from mice with altered retinal activity revealed that spontaneous retinal waves occurring prior to visual experience also play a role in shaping the connectivity of the non-image forming circuit. Overall, these findings contribute to a deeper understanding of the mechanisms governing activity-dependent axon refinement during the establishment of the visual circuit.

neuroscience↗

bioRxiv2020

Molecular development of muscle spindle and Golgi tendon organ sensory afferents revealed by single proprioceptor transcriptome analysis

Anatomical and physiological analyses have long revealed differences between proprioceptive groups Ia, II, and Ib sensory neurons, yet the molecular correlates of these three muscle afferent subtypes remain unknown. We performed single cell RNA sequencing of genetically identified adult proprioceptors and, using unbiased bioinformatics approaches, detected five molecularly distinct neuronal clusters. Validation of cluster-specific transcripts in dorsal root ganglia (DRG) and skeletal muscle provides evidence these clusters correspond to functionally distinct muscle spindle (MS) or Golgi tendon organ (GTO) afferent proprioceptors. Remarkably, while we uncovered just one type of GTO afferents, four of the five clusters represent MS afferents, thus demonstrating a previously unappreciated diversity among these muscle proprioceptors. In vitro electrophysiological recordings reveal just two broadly distinct proprioceptor types, and suggest that the refinement of functional subtype diversity may occur along multiple axes of maturation. Lineage analysis between proprioceptor transcriptomes at different developmental stages show little or no correlation for transcripts that define adult MS or GTO afferents, supporting the idea that proprioceptor subtype identity emerges late in development. Together, our data provide the first comprehensive molecular signature for groups Ia and II MS afferents and group Ib GTO afferents, and offer new strategies for genetic interrogation of the role of these individual proprioceptor subtypes in regulating voluntary motor behavior.

neuroscience↗