A network of Notch-dependent and -independent her genes controls neural stem and progenitor cells in the zebrafish thalamic proliferation zone

Abstract

Neural proliferation zones mediate brain growth, and employ Delta/Notch signaling and HES/HER transcription factors to balance neural stem cell (NSC) maintenance and generation of progenitors and neurons. We investigated Notch-dependency and function of her genes in the thalamic proliferation zone of developing zebrafish larvae. Nine Notch-dependent genes, her2, her4.1-5, her12, her15.1-2, and two Notch-independent genes, her6, her9, are differentially expressed, and define distinct NSC and progenitor populations. her6 prominently executes patterning information to maintain NSCs and the zona limitans intrathalamica Shh signaling activity. her6, her9 double mutants reveal that Notch-independent her genes predominantly regulate NSC maintenance and transition into the progenitor pool. Surprisingly, combined deletion of all Notch-dependent her genes does not affect NSCs or progenitor formation. Combined genetic manipulation of up to eleven Notch-dependent and -independent her genes revealed that Notch-dependent her genes may regulate progenitor progression into neurogenesis, but not progenitor generation itself. The her gene network is partially redundant, with Notch-independent her genes better substituting for loss of Notch-dependent genes than vice versa. Together, her gene regulatory feedback loops and crossregulation contribute to the observed robustness of NSC maintenance.

Her9 controls the stemness properties of the hindbrain boundary cells

“…Its expression is enriched in boundary cells compared to rhombomere compartments at early stages, and it remains mainly in proliferating radial glial cells of lateral domains all along the AP axis at later stages. Our results support the developmental strategy othat different Hes/Her genes maintain distinct neural progenitor populations (Chapouton et al , 2006; Stigloher et al , 2008; Sigloch et al , 2023) establishing the neurogenic asynchrony in neural tissues. Hindbrain boundaries initially behave as a pool of non-neurogenic progenitors expressing her9 in a Notch-independent manner.…”

“…Our results support the developmental strategy othat different Hes/Her genes maintain distinct neural progenitor populations (Chapouton et al, 2006;Stigloher et al, 2008;Sigloch et al, 2023) establishing the neurogenic asynchrony in neural tissues. Hindbrain boundaries initially behave as a pool of non-neurogenic progenitors expressing her9 in a Notchindependent manner.…”

SINGLE CELL RESOLUTION OF THE ADULT ZEBRAFISH INTESTINE UNDER CONVENTIONAL CONDITIONS, AND IN RESPONSE TO AN ACUTEVIBRIO CHOLERAEINFECTION

“…Among the transcriptional clusters, we identified leukocytes, differentiated stromal cells, and nine IEC types that included a cycling population enriched for the Notch mediator her15.1 (Figure 2B), a pan-stem cell marker in zebrafish [35][36][37] . Fluorescence in situ hybridization showed that her15.1+ cells are proliferative residents of the interfold base (Figure 2C), as expected for intestinal stem cells.…”

Neurog1 and Olig2 integrate patterning and neurogenesis signals in development of zebrafish dopaminergic and glutamatergic dual transmitter neurons

“…6C -D'', white arrowheads). Thus, Olig2 is negatively regulating the expression of her2 in the hypothalamus/posterior tuberculum, which is positively regulated by Notch signaling (Cheng et al, 2015;Sigloch et al, 2023). To determine whether Shh signaling is involved in regulation of olig2 expression in the posterior tuberculum/hypothalamus, we inhibited Shh signaling using Cyclopamine from 24 to 48 hpf (Fig.…”