Molecular Logic of Hypothalamus Development

Abstract

The hypothalamus is a central regulator of physiological homeostasis. During development, multiple transcription factors coordinate the patterning and specification of hypothalamic nuclei. However, the molecular mechanisms controlling hypothalamic patterning and cell fate specification are poorly understood. To identify genes that control these processes, we have previously used single-cell RNA sequencing (scRNA-Seq) to profile mouse hypothalamic gene expression across multiple developmental time points and established database HyDD (Hypothalamus Developmental Database). We next used HyDD to characterize multiple mutant lines targetting key transcription factors that came out from our scRNA-Seq database (Nkx2.2, Dlx1/2, Isl1, Foxd1, Lhx2), and was able to comprehensively characterize mutants that have altered hypothalamic patterning. Our phenotype result supports a modified columnar model of organization for the diencephalon, where prethalamus and hypothalamus are situated in adjacent dorsal and ventral domains of the anterior diencephalon. Furthermore, using our mouse hypothalamus as a guideline, we are comparing scRNA-Seq dataset of developing chicken, zebrafish and human hypothalamus, to identify evolutionarily conserved and divergent region-specific gene regulatory networks. Lastly, we are improving mouse HyDD, in order to characterize adult hypothalamus neuronal subtypes.