In vivo clonal analysis reveals spatiotemporal regulation of thalamic nucleogenesis

Abstract

The thalamus, a crucial regulator of cortical functions, is composed of many nuclei arranged in a spatially complex pattern. Thalamic neurogenesis occurs over a short period during embryonic development. These features have hampered the effort to understand how regionalization, cell divisions and fate specification are coordinated and produce a wide array of nuclei that exhibit distinct patterns of gene expression and functions. Here, we performed an in vivo clonal analysis to track the divisions of individual progenitor cells and spatial allocation of their progeny in the developing thalamus. Quantitative analysis of clone compositions revealed evidence for sequential generation of distinct sets of thalamic nuclei that are associated with the location of the founder cell. Furthermore, we identified intermediate progenitor cells that produced two to four neurons populating more than one thalamic nuclei, indicating a late specification of nuclear fate. Our study reveals an organizational principle that governs the spatial and temporal progression of cell divisions and fate specification, and provides a framework for studying cellular heterogeneity and connectivity in the thalamus.

A repeated molecular architecture across thalamic pathways

“…Though our data come from adult mice, thalamic gene expression is known to be highly dynamic during development 42 . Prior work has shown a link between a thalamic neuron's birth date and its resulting spatial location and calcium binding protein expression (Calb1, Calb2 and Pvalb), including reports of a latero-medial gradient of neuronal birth date in thalamus [43][44][45][46] . Speculatively, this suggests a sequential development of the topogenetic axis identified here.…”

Relationships between neuronal birthdates and tonotopic positions in the mouse cochlear nucleus

“…Spatiotemporal gradients of neurogenesis are recurrent themes in many regions of the developing nervous system, including cortical neurons in the neocortex (Sansom & Livesey, ), mitral cells in the olfactory bulb (Imamura, Ayoub, Rakic, & Greer, ), thalamic neurons in the thalamus (Nakagawa & Shimogori, ; Wong et al, ), dopaminergic neurons in the midbrain (Bayer, Wills, Triarhou, & Ghetti, ), and pyramidal cells and dentate granule cells in the hippocampus (Bayer, ; Martin, Tan, & Goldowitz, ). In several regions of the auditory pathway, functionally distinct neurons are arranged in a topographic gradient according to their birthdates, such as SGNs in the cochlea and neurons in the inferior colliculus (Altman & Bayer, ; Koundakjian et al, ; Matei et al, ; Ruben, ).…”

TCF7L2 regulates postmitotic differentiation programs and excitability patterns in the thalamus

“…The habenula controls reward-and aversion-driven behaviours by connecting cortical and subcortical regions with the monoamine system in the brainstem (Benekareddy et al, 2018;Hikosaka, 2010). During postmitotic differentiation, thalamic and habenular neurons segregate into discrete nuclei (Shi et al, 2017;Wong et al, 2018), develop a variety of subregional identities (Guo and Li, 2019;Nakagawa, 2019;Phillips et al, 2019), extend axons toward their targets (Hikosaka et al, 2008;López-Bendito, 2018), and acquire electrophysiological characteristics postnatally (Yuge et al, 2011). The knowledge of the mechanisms that control postmitotic development in this region is important, because its functional dysconnectivity, which possibly originates from the period of postmitotic maturation, is implicated in schizophrenia, autism and other mental disorders (Browne et al, 2018;Steullet, 2019;Whiting et al, 2018;Woodward et al, 2017).…”