Biology subjects

Rastegar, S.

Publications and source records attributed to Rastegar, S..

6 recordsLinked to original sources

bioRxiv2025

Multiple cis-regulatory elements collaborate to control mdka expression in zebrafish adult telencephalic neural stem cells during constitutive and regenerative neurogenesis

Zebrafish is a powerful animal model for studying nervous system regeneration due to its remarkable regenerative abilities and the availability of diverse molecular tools. After telencephalic brain injury, neural stem cells (NSCs) in the ventricular zone (VZ) become activated, proliferate, and generate new neurons essential for brain repair. However, the molecular mechanisms regulating these processes remain unclear. Here, we investigate the transcriptional regulation of midkine-a (mdka), a heparin-binding growth factor gene encoding the secreted protein Midkine-a (Mdka), which is upregulated after injury in radial glial cells (RGCs), the bona fide NSCs of the adult zebrafish telencephalon. Using genome-wide bioinformatic analysis, we identified six putative cis-regulatory elements (CREs) associated with mdka. Transgenic assays revealed that these CREs coordinate mdka expression during both development and regeneration. In the zebrafish embryo, CRE2, CRE3, CRE4, and CRE6 are required for EGFP expression in the nervous system, with CRE3 showing the strongest activity. In the adult telencephalon, CRE2, CRE4, and CRE6 are active in NSCs, with CRE2 best mimicking mdka expression at the ventricular zone. Importantly, individual CREs could not fully reproduce endogenous mdka expression, especially under regenerative conditions. In contrast, a combined CRE2346 construct closely recapitulated mdka expression in both the embryo and adult telencephalon under homeostatic conditions. These results suggest that mdka expression is controlled by a modular and cooperative cis-regulatory architecture that enables precise gene regulation during development, telencephalon homeostasis, and regeneration.

developmental biology↗

bioRxiv2023

Temporal single-cell transcriptomic analysis of the sox1a:eGFP transgenic line identified the lateral floor plate progenitor cells as the origin of intraspinal serotonergic neurons

The Sox family of transcription factors plays a crucial role in the development of the vertebrate nervous system. In the zebrafish embryo, sox1 genes are expressed in neural progenitor cells and neurons of the ventral spinal cord. We recently reported that the loss of function of sox1a and sox1b leads to a significant decline in a subtype of V2 neurons, called V2s, in zebrafish. Here, a single-cell RNA sequencing approach was used to analyse the transcriptome of sox1a lineage progenitors and neurons in the zebrafish spinal cord at four different time points during the first five days of embryonic development, using the Tg(sox1a:eGFP) line. In addition to the previously described sox1a-expressing neurons, we found that sox1a is also expressed in late-developing intraspinal serotonergic neurons (ISNs). Analysis of developmental trajectories from single-cell data and depletion of lateral floor plate (LFP) cells by nkx2.9 morpholino knockdown suggest that ISNs arise from LFP precursor cells. Pharmacological inhibition of the Notch signalling pathway indicates that this pathway is required for the negative regulation of the development of LFP progenitor cells into ISN populations. Our results show that the zebrafish LFP is a precursor domain that longitudinally gives rise to ISNs in addition to the previously described KA" and V3 interneurons.

developmental biology↗

bioRxiv2021

Integrative annotation of genomic features reveal functional elements and epigenetic landscapes in the developing zebrafish

Zebrafish, a popular model for embryonic development and for modelling human diseases, has so far lacked a systematic functional annotation programme akin to those in other animal models. To address this, we formed the international DANIO-CODE consortium and created the first central repository to store and process zebrafish developmental functional genomic data. Our Data Coordination Center (https://danio-code.zfin.org) combines a total of 1,802 sets of unpublished and reanalysed published genomics data, which we used to improve existing annotations and show its utility in experimental design. We identified over 140,000 cis-regulatory elements in development, including novel classes with distinct features dependent on their activity in time and space. We delineated the distinction between regulatory elements active during zygotic genome activation and those active during organogenesis, identifying new aspects of how they relate to each other. Finally, we matched regulatory elements and epigenomic landscapes between zebrafish and mouse and predict functional relationships between them beyond sequence similarity, extending the utility of zebrafish developmental genomics to mammals.

developmental biology↗

bioRxiv2021

Neuron-radial glial cell communication via BMP/Id1 signaling maintains the regenerative capacity of the adult zebrafish telencephalon

The mechanisms of the management of the neural stem cell (NSC) pool underlying the regenerative capacity of the adult zebrafish brain are not understood. We show that Bone Morphogenetic Proteins (BMPs) which are exclusively expressed by neurons in the adult telencephalon and the helix-loop-helix (HLH) transcription co-regulator, Inhibitor of differentiation 1 (Id1), control quiescence of NSCs. Upon injury, lack of id1 function leads to an initial over-proliferation and subsequent loss of NSCs and the regenerative capacity. BMP/Id1 signaling up-regulates the transcription factor her4.1 which is also a target of Notch signaling mediating short-range control of NSC quiescence. Hence, the two signaling systems converge onto Her4.1. Our data show that neurons feedback on NSC proliferation. BMP1/Id1 signaling appears as the predominant safeguard of the NSC pool under regenerative conditions while Notch signaling is sufficient to maintain NSCs under homeostatic baseline neurogenesis in the uninjured animal.

developmental biology↗

bioRxiv2020

Multi-dimensional transcriptome analysis reveals modulation of cholesterol metabolism as highly integrated response to brain injury.

BackgroundZebrafish is an attractive model to investigate regeneration of the nervous system. Despite major progress in our understanding of the underlying processes, the transcriptomic changes are largely unknown. We analysed the transcriptome of the regenerating telencephalon for changes in the expression of mRNAs, their splice variants and investigated the putative role of regulatory RNAs in the modulation of these transcriptional changes. ResultsProfound changes in the expression of genes and their splice variants engaged in many distinct processes were observed. As exemplified by the coordinated regulation of the cholesterol synthesizing enzymes and transporters, the genome responded to injury of the telencephalon in a multi-tiered manner with distinct and interwoven changes in expression of enzymes, transporters and their regulatory molecules. This coordinated genomic response involved a decrease of the mRNA of the key transcription factor SREBF2, induction of microRNAs (miR- 182, miR-155, miR-146, miR-31) targeting cholesterol genes, shifts in abundance of splice variants as well as regulation of long non-coding RNAs. ConclusionsDifferential transcription and splicing are important processes in response to injury of the telencephalon. Cholesterol metabolism is switched from synthesis to relocation of cholesterol. Based on our in silico analysis, this switch involves complementary and synergistic inputs by different regulatory principles. Our studies suggest that adaptation of cholesterol metabolism appears to be a key process involved in regeneration of the injured zebrafish brain.

bioinformatics↗

bioRxiv2019

BMP signaling regulates Id1 mediated neural stem cell quiescence in the adult zebrafish brain via a phylogenetically conserved enhancer module

In the telencephalon of adult zebrafish, the inhibitor of DNA binding 1 (id1) gene is expressed in radial glial cells (RGCs), behaving as neural stem cells (NSCs), during constitutive and regenerative neurogenesis. Id1 controls the balance between resting and proliferating states of RGCs by promoting quiescence. Here, we identified a phylogenetically conserved cis-regulatory module (CRM) mediating the specific expression of id1 in RGCs. Systematic deletion mapping and mutation of conserved transcription factor binding sites in stable transgenic zebrafish lines reveal that this CRM operates via conserved smad1/5 and 4 binding motifs (SBMs) under both homeostatic and regenerative conditions. Transcriptome analysis of injured and uninjured telencephala as well as pharmacological inhibition experiments identify a crucial role of bone morphogenetic protein (BMP) signaling for the function of the CRM. Our data highlight that BMP signals control id1 expression and thus NSC proliferation during constitutive and induced neurogenesis.

developmental biology↗