Biology subjects

Strahle, U.

Publications and source records attributed to Strahle, U..

3 recordsLinked to original sources

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↗

bioRxiv2019

Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress

Whole-genome sequencing was performed on patients with severe deafness and early-onset cataracts as part of a neurological, sensorial and cutaneous novel syndrome. A unique deep intronic homozygous variant in the PSMC3 gene (c.1127+337A>G, p.Ser376Argfs15*), encoding the 26S proteasome ATPase ring subunit 5 (Rpt5) was identified leading to the transcription of a cryptic exon. Patients fibroblasts exhibited impaired protein homeostasis characterized by accumulation of ubiquitinated proteins suggesting severe proteotoxic stress. Indeed, the TCF11/Nrf1 transcriptional pathway allowing proteasome recovery after proteasome inhibition is permanently activated in the patients fibroblasts. Upon chemical proteasome inhibition this pathway is however impaired. These cells were unable to compensate for proteotoxic stress although a higher proteasome content. Two different zebrafish studies led to inner ear development anomalies as well as cataracts. PSMC3 proteasome subunit dysfunction leads to various neurological manifestations, early onset cataracts and deafness and suggest that Rpt5 plays a major role in inner ear, lens and central nervous system development.

genetics↗

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↗