Klf10 Regulates the Emergence of Glial Phenotypes During Hypothalamic Development

Abstract

Glial cells play a pivotal role in the Central Nervous System (CNS), constituting most brain cells. Gliogenesis, crucial in CNS development, occurs after neurogenesis. In the hypothalamus, glial progenitors first generate oligodendrocytes and later astrocytes. However, the precise molecular mechanisms governing the emergence of glial lineages in the developing hypothalamus remain incompletely understood. This study reveals the pivotal role of the transcription factor KLF10 in regulating the emergence of both astrocyte and oligodendrocyte lineages during embryonic hypothalamic development. Through transcriptomic and bioinformatic analyses, we identified novel KLF10 putative target genes, which play important roles in the differentiation of neurons, astrocytes, and oligodendrocytes. Notably, in the absence of KLF10, there is an increase in the oligodendrocyte population, while the astrocyte population decreases in the embryonic hypothalamus. Strikingly, this decline in the number of astrocytes persists into adulthood, indicating that the absence of KLF10 leads to an extended period of oligodendrocyte emergence while delaying the appearance of astrocytes. Our findings also unveil a novel signaling pathway for Klf10 gene expression regulation. We demonstrate that Klf10 is a target of CREB and that its expression is upregulated via the BDNF-p38-CREB pathway. Thus, we postulate that KLF10 is an integral part of the hypothalamic developmental program that ensures the correct timing for glial phenotypes' generation. Importantly, we propose that the Klf10^−/− mouse model represents a valuable tool for investigating the impact of reduced astrocyte and microglia populations in the homeostasis of the adult hypothalamus.