Clonal Analysis Of Thalamus Development And Function

The thalamus, with its intricate cortical, subcortical, and cerebellar connections, is a pivotal network node in relaying and modulating sensory and motor signals to the cortex as well as supporting higher-order cognitive functions. It is composed of more than 30 cytoarchitectonically and functionally distinct nuclei, each with a different anatomical connectivity pattern. In particular, every sensory modality (with the exception of olfaction) relies on a first order (FO) thalamic nucleus that receives peripheral signals and projects to the primary cortical area, and a higher order (HO) thalamic nucleus that relays information from one cortical area to another cortical area. While the order-specific nuclear organization across different modalities provides an influential framework for understanding thalamic structure and function, very little is known about the mechanisms responsible for its establishment. Previous studies have shown that lineage relationship plays an instructive role in guiding the structural and functional assembly of the cortex, a laminated structure reciprocally interconnected with the thalamus. However, it remains unclear whether lineage relationship influences the structural formation and functional organization of the generally non-laminated thalamus. To address this, I performed a systematic clonal analysis of mouse thalamus assembly using mosaic analysis with double markers (MADM) and Cre-dependent retroviral labeling. I found that individual radial glial progenitors in the developing thalamus actively divide and generate a cohort of neuronal progeny that exhibits striking spatial configuration and nuclear occupation related to thalamic functionality. While the anterior clonal clusters display relatively more tangential dispersion and contribute predominantly to nuclei with cognitive functions, the medial ventral posterior clonal clusters form prominent radial arrays and contributes mostly to nuclei with sensory/motor-related activities. Moreover, neurons occupying the FO or HO sensory/motor-related nuclei across different modalities are largely segregated clonally and exhibit distinct gene expression profiles. Notably, the spatial distribution of clones depends on the SHH signaling activity that exhibits a gradient in the developing thalamus. Together, our study reveals a previously unknown ontogenetic logic for the structural and functional assembly of the mammalian thalamus