Biology subjects

Driever, W.

Publications and source records attributed to Driever, W..

6 recordsLinked to original sources

bioRxiv2026

Notch-independent Her6 contributes to control of neural stem cell maintenance by shifting Notch signaling from lateral inhibition towards lateral induction mode

The growing brain faces the challenge to establish neural stem cell (NSC) populations that accomplish both stable NSC maintenance and dynamic generation of progenitors. Lineage-specific scRNA-seq and time series transcriptome analyses upon overexpression of Notch signaling components in the larval zebrafish brain reveal differential contributions of Notch signaling and Notch-independent Her6, a HES1 homolog, to NSC regulation. Notch signaling and Her6 distinctly regulate cell cycle genes to control G0/G1 or G2 exit and promote quiescence. Her6 and Notch activity combined differentially control delta, jagged, lfng and notch3 expression to potentially shift Notch signaling from Delta-driven lateral inhibition to Jagged-Notch3-mediated lateral induction. We propose that Her6 integrates cell-autonomous lineage-based information and lateral induction-mediated non-autonomous self-organization of neural proliferation zones. Her6-dependent lateral induction maintains persistent NSC patches in ventricular compartments with ongoing neurogenesis, and establishes coherent populations of long-term NSCs in active proliferation zones.

developmental biology↗

bioRxiv2026

Parameters for stable Notch-independent Her6 oscillations across a frequency spectrum in neural stem cell populations

Neural proliferation zones drive the major growth phases of the vertebrate brain. Notch signaling and HES/Her transcription factors control neural stem cell (NSC) maintenance and neurogenesis, however the dynamic regulation of neural proliferation zones to sustain growth is not well understood. Notch-independent expression of the zebrafish HES1 homolog her6 in the larval brain is required for NSC maintenance and growth. We generated an mNeonGreen knock-in into the her6 locus and quantified Her6-mNeonGreen oscillations in vivo in distinct NSC populations. Her6 oscillates cell-autonomously across a broader frequency range, unaffected by inhibition of Notch signaling, and robustly reinitiated after experimental perturbations. Mathematical modelling reveals that Her6 oscillations prevail only when both transcript and protein degradation rate constants are equal. These intrinsic control parameters may have evolved to enable the Her6 oscillator to robustly maintain stemness during proliferative phases irrespective of local Notch signaling cues, and to provide for lineage stability while retaining plasticity for lineage progression.

developmental biology↗

bioRxiv2025

A genetic model for development, physiology and behavior of zebrafish larvae devoid of catecholamines

Dopamine and noradrenaline have conserved roles in control of physiology and behaviors of vertebrates. However, vertebrate genetic systems completely devoid of catecholamines are not available. We have generated a genetic zebrafish model completely devoid of catecholamines by combining mutations in all three genes involved in L-DOPA synthesis: the tyrosine hydroxylase genes th and th2, and tyrosinase tyr. We found catecholamine-deficient zebrafish larvae to be viable and to develop an anatomically normal nervous system including catecholaminergic neuron somata and projections, albeit with reduced cell numbers detected in some clusters. In contrast, selected physiological functions that depend on catecholamines are impaired, including hatching and heart rate regulation upon temperature challenges. Spontaneous locomotion and optomotor behaviors are also impaired. Despite the changes observed, it is surprising that larvae develop a largely normal behavioral repertoire. Our model will be useful to investigate how physiology and neural circuit function are regulated in catecholamine deficient larvae.

developmental biology↗

bioRxiv2025

Analysis of lhx8a, isl1, pax6a/b, calb2a and sst7 Reveals that Dopaminergic Neurons in the Zebrafish Subpallium Belong to the Extended Amygdala

The amygdala is a heterogenous multinuclear telencephalic structure critical for motivated and emotion-related behaviors in vertebrates. In ray-finned fish (actinopterygii) like the teleost zebrafish, a telencephalic outward growing process called eversion makes defining amygdaloid territories particularly challenging. Teleosts are also peculiar in that they develop prominent dopaminergic neuron groups in the subpallium, which are absent from tetrapods. To shed light on amygdala organization in teleosts, we pursued an evolutionary-developmental approach focusing on the topological origin of subpallial dopaminergic neurons. Specifically, we analyzed developmental expression patterns of Tyrosine hydroxylase in conjunction with pax6a+b, isl1a, nkx2.1, lhx8a, calb2a as telencephalic topology markers in brains of 5- and 30-day-old zebrafish (Danio rerio, Teleostei). Our results reveal, that the subpallial dopaminergic neurons develop within a pax6a negative dorsal subpallial domain (Vdd), which forms a primordial portion of the extended amygdala, including the medial amygdala and the anterior bed nucleus of the stria terminalis. Moreover, these dopaminergic neurons differentially coexpress calb2a and sst7, indicating population heterogeneity and potentially functional diversity. Our data also show that the zebrafish extended amygdala is formed by the dorsal LGE-like Vdd, which is subdivided into a Vdd2 subdivision that may correspond to the extended medial amygdala, including the bed nucleus of the stria terminalis, and forms the pallial-subpallial border region, and a more ventral Vdd1 that is pax6a positive and that corresponds to the central amygdala. Our work contributes to understanding development and evolution of the amygdala, and provides a foundation for functional analysis of the newly defined dopaminergic subtypes of the extended amygdala.

neuroscience↗

bioRxiv2023

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

Dopaminergic neurons develop in distinct neural domains by integrating local patterning and neurogenesis signals. While the proneural proteins Neurog1 and Olig2 have been previously linked to development of dopaminergic neurons, their dependence on local prepatterning and specific contributions to dopaminergic neurogenesis are not well understood. Here, we show that both transcription factors are differentially required for the development of defined dopaminergic glutamatergic subpopulations in the zebrafish posterior tuberculum, which are homologous to A11 dopaminergic neurons in mammals. Both Olig2 and Neurog1 are expressed in otpa expressing progenitor cells and appear to act upstream of Otpa during dopaminergic neurogenesis. Our epistasis analysis confirmed that Neurog1 acts downstream of Notch signaling, while Olig2 acts downstream of Shh, but upstream and/or in parallel to Notch signaling. Furthermore, we identified Olig2 to be an upstream regulator of neurog1 in dopaminergic neurogenesis. This regulation occurs through Olig2-dependent repression of the proneural repressor and Notch target gene her2. Our study reveals how Neurog1 and Olig2 integrate local patterning signals, including Shh, with Notch neurogenic selection signaling, to specify the progenitor population and initiate neurogenesis and differentiation of A11-type dopaminergic neurons.

developmental biology↗

bioRxiv2022

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

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.

developmental biology↗