Overview
The somatosensory system encompasses a diverse array of neurons responsible for detecting a variety of sensations throughout the viscera, muscle, and skin. Everyday activities, such as picking up a morning cup of coffee involves a complex interplay of sensory functions. This includes discerning the cup’s texture (discriminative touch), understanding the spatial orientation of your fingers and arm relative to your mouth (proprioception), and ensuring the coffee is not too hot before taking a sip (temperature and noxious stimuli). Despite its importance in our daily lives, the development of these diverse cell types, and consequently the function of these neurons, is not well understood. The goal of the Lai Lab is to understand the formation and wiring of these neurons, specifically at the level of the peripheral sensory neurons and spinal cord neurons, to elucidate the developmental and circuit mechanisms that give rise to these complex sensations.
Developmental Spinal Cord Atlas
The developing spinal cord has long been a classic model for unraveling neurodevelopmental mechanisms underlying cell fate decisions. However, establishing the connection between developmental cell types and their adult counterparts is challenging. Adult cell types have typically lost expression of their embryonic transcription factors making it difficult to link adult spinal cord cell types to their developmental progenitor domains. Our objective is to address this gap in knowledge by tracking the transcriptional, epigenetic, and spatial distribution changes of developmental lineages over time using genetic lineage tracing of molecularly-defined progenitor domains. A comprehensive understanding of cell types resulting from common developmental lineages can reveal true structural and functional complexity of spinal cord circuits that are often not reflected in single-cell transcriptomics of adult tissue.
Nociceptor development and maintenance
The dorsal root ganglion (DRG) contains the cell bodies of all the somatosensory neurons for the body. However, the molecular mechanisms that lead to diversification of somatosensory neurons are still unknown. Our lab is interested in understanding the developmental mechanisms of DRG cell type specification. We revisited classical birth dating studies and found that different nociceptor subtypes are born more continuously over embryogenesis than previously thought (Landy et al., Dev Bio, 2021). We have also focused on transcription factor pathways leading to cell type specification of nociceptors. In particular, Prdm12, a transcription factor that has been identified in humans to cause congenital insensitivity to pain, is essential for specifying nociceptive sensory neurons. We found that although lack of Prdm12 during development leads to a painless phenotype in mice, Prdm12 serves a different function in the adult (Landy et al., Cell Reports, 2021). Our lab continues to leverage our expertise in molecular and developmental mechanisms of the DRG to understand how PRDM12 function changes from embryogenesis to adulthood. Insights gained from our research will allow researchers to develop strategies for replacing DRG neurons that are lost in peripheral injury or degenerative disease.
Proprioceptive circuit dissection
Proprioception, the sense of limb and body position, generates a body map that is critical to generating proper motor output. Despite decades of research, it is still unknown precisely how this sense allows us to achieve controlled motor function.
We are focused on understanding the logic of proprioceptive circuits relayed through the spinal cord. Using molecular genetic tools in mice, we have discovered novel aspects of the anatomy of direct, long-range spinocerebellar pathways and locally-projecting proprioceptive circuits (Yuengert et al., Cell Reports, 2015; Pop et al., J Neurosci, 2022). We are currently disentangling the contribution of distinct populations of direct and indirect cerebellar-projecting neurons to understand their role in mediating proprioception.