Biology subjects

Heermann, S.

Publications and source records attributed to Heermann, S..

7 recordsLinked to original sources

bioRxiv2024

Holoprosencephaly and Cyclopia in bmp7b and bmpr1ba Crispant zebrafish

Holoprosencephaly (HPE) is the most frequent developmental disorder of the forebrain. In HPE, the early single anlage of the forebrain, the Anterior Neural Plate (ANP) which encompasses the future telencephalon and eye field, fails to divide. BMP signaling and antagonism are overall important for nervous system development. The focus of this study was on the role of the ligand bmp7b and the receptor bmpr1ba during forebrain development. The zebrafish loci of bmp7b and bmpr1ba were targeted transiently with CRISPR/Ca9. Crispants for both bmp7b and bmpr1ba presented HPE and cyclopia, one central eye. Subsequently, the ANP was addressed in bmp7b Crispants. The morphology of the eye field was affected, with important markers, rx3, six3b and cxcr4a expressed condensed at the midline. Induced expression of bmp4 is also known to result in HPE. Such bmp4 induction altered the expression of bmpr1ba. Zebrafish Crispants for bmp7b and bmpr1ba can be used as a novel HPE model. A challenge in future analyses will be the penetrance of phenotypes in Crispants. Advantages are, however, that analyses can be conducted anywhere, without the need of mutant lines. One important aspect for future analysis will be the role of individual bmp ligands, receptors and antagonists in forebrain development.

developmental biology↗

bioRxiv2024

Different ophthalmologic findings in induced models of Holoprosencephaly in zebrafish

Early forebrain development is a fascinating process. The fate of brain function but also the fate of visual perception largely depends on it. Holoprosencephaly (HPE) is the most frequent developmental disorder of the forebrain, during which the separation of the early precursor domains is hampered. A spectrum of clinical manifestations is seen with severe forms like alobar HPE and less severe forms like lobar HPE. The ophthalmologic findings which accompany HPE are also found as a spectrum that ranges from ocular hypotelorism and synophthalmia to cyclopia and anophthalmia. Here we ask, whether anophthalmia or cyclopia is the default ophthalmologic finding in severe forms of HPE. In this brief analysis, we made use of a recently established zebrafish model of severe HPE, based on BMP ligand induction. Such BMP ligand induction resulted in anophthalmia. We attenuated the induction protocol to investigate whether the anophthalmia phenotype could be changed into a cyclopic phenotype. We found a spectrum of ocular phenotypes, ocular hypotelorism, and also cases of synophthalmia and cyclopia. This suggests that in the context of this HPE model the strongest ophthalmologic phenotype is anophthalmia and less severe forms are cyclopia, synophthalmia and ocular hypotelorism.

developmental biology↗

bioRxiv2023

BMP7 promotes cardiomyocyte regeneration

Zebrafish has a remarkable and lifelong ability for cardiac regeneration after severe damage, whereas mammals lose their innate capacity for heart regeneration during early postnatal development. This study aimed to investigate whether the decreased production of growth factors during postnatal mammalian development contributes to the exit of cardiomyocytes from the cell cycle and the reduction in cardiac regenerative ability. We identified growth factors with declining expression levels during early postnatal life in the mouse model and assessed the pro-proliferative ability of these factors on neonatal murine primary cardiomyocytes in vitro. Our findings confirmed the previously reported pro-proliferative effects of NRG1, IL1b, RANKL, IGF2 and IL6, while also identifying novel potential pro-regenerative growth factors. Among them, BMP7 exhibited the most pronounced efficacy. Bmp7 knockdown interfered with the proliferation of neonatal mouse cardiomyocytes in culture and adult bmp7 mutant zebrafish displayed reduced cardiomyocyte proliferation during heart regeneration, indicating that Bmp7 is crucial for cardiomyocyte proliferation in the regenerative stages of mouse and zebrafish hearts. Conversely, bmp7 overexpression was sufficient to boost cardiomyocyte cycling in regenerating zebrafish hearts, while BMP7 administration stimulated mouse cardiomyocyte cycling at postnatal-day-7, when cardiomyocytes ceased to proliferate, and enhanced cardiomyocyte regeneration in vivo in adult mice following myocardial infarction. Mechanistically, BMP7-induced proliferation was mediated by type I BMP receptors BMPR1A and ACVR1, and type II receptors ACVR2A and BMPR2. Downstream signalling involved SMAD5, ERK and AKT. In conclusion, the administration of BMP7 holds promise as a strategy to stimulate heart regeneration following cardiac injury.

molecular biology↗

bioRxiv2022

Early eye and forebrain development are facilitated by Bone Morphogenetic Protein antagonism

Vision likely is our most prominent sense and a correct development of the eye is at its basis. Early eye development is tightly connected to the development of the forebrain. A single eye field and the prospective telencephalon are situated within the anterior neural plate (ANP). If development is running correctly both are split and consecutively two optic vesicles and two telencephalic lobes emerge. If hampered, the domain is remaining condensed at the midline. This affection of development is termed Holoprosencephaly (HPE). The classical ocular finding associated with intense forms of HPE is cyclopia, one central eye. We found that antagonists of Bone morphogenetic proteins (BMP) are important to facilitate proper forebrain and eye field cleavage. Experimental induction of a BMP ligand results in HPE and the analyses of the ANP indicated a severe form. We further found anophthalmia instead of cyclopia associated with the present HPE phenotype. We identified retinal progenitors stuck in the forebrain domain, which we termed crypt-oculoid. Our data further suggest that the process of basal constriction of retinal progenitors is hampered by elevated levels of the BMP ligand. This likely is the reason for anophthalmia instead of cyclopia in this present case of HPE.

developmental biology↗

bioRxiv2021

BMP signaling interferes with optic chiasm formation and retinal ganglion cell pathfinding in zebrafish

Decussation of axonal tracts is an important hallmark of vertebrate neuroanatomy resulting in one brain hemisphere controlling the contralateral side of the body and also computing the sensory information originating from that respective side. Here, we show that BMP interferes with optic chiasm formation and RGC pathfinding in zebrafish. Experimental induction of BMP4 at 15 hpf results in a complete ipsilateral projection of RGC axons and failure of commissural connections of the forebrain in part being the result of an interaction with shh signaling, transcriptional regulation of midline guidance cues and an affected optic stalk morphogenesis. Experimental induction of BMP4 at 24 hpf, resulting in only a mild repression of forebrain shh ligand expression but in a broad expression of pax2a in the diencephalon, does not per se prevent RGC axons from crossing the midline. It nevertheless shows severe pathologies of RGC projections e.g. the fasciculation of RGC axons with the ipsilateral optic tract resulting in the innervation of one tectum by two eyes or the projection of RGC axons in the direction of the contralateral eye.

developmental biology↗

bioRxiv2017

Optic Fissure Margin Morphogenesis Sets The Stage For Consecutive Optic Fissure Fusion, Pioneered By A Distinct Subset Of Margin Cells Using A Hyaloid Vessel As Scaffold

The optic fissure is a transient gap in the developing optic cup of vertebrates. Persisting optic fissures, coloboma, are a frequent reason for blindness in children. Although many genes have been linked to coloboma, it has remained unclear how the two bi-layered epithelia comprising the optic fissure margins are fusing to form a continuous neuroretina and retinal pigmented epithelium (RPE) respectively. Besides, highly variable morphologies of coloboma phenotypes strongly argue for a diverse set of underlying pathomechanisms.\n\nHere we investigated the contribution of the individual cell types with 4D in vivo time-lapse analyses using zebrafish (Danio rerio). This allowed defining the respective roles of the participating tissues and cell populations and their activities during fissure morphogenesis, contact formation between the margins as well as during fusion.\n\nWe show that optic fissure closure is initiated by a bilateral tissue flow partially in continuation of the dynamic optic cup morphogenesis but additionally including a tissue flow from the optic stalk. This process is followed by the setup of specific fissure margins by a distinct cell population translocating from of the optic stalk. The morphological fusion is triggered by in an EMT-like disassembly of the fissure margin driven by bi-potential pioneer cells that ultimately take the fate of both, neuroretina and RPE respectively. The consecutive fusion and re-epithelialization transforms the two initially separated epithelial bilayers into the two continuous layers of neuroretina and RPE. The processes described here in detail represents a fundamental mechanism of the seamless connection of adjacent multilayered epithelia and is highly reminiscent of other fusion processes, like palatal shelf fusion with key relevance for development and growth.

developmental biology↗

bioRxiv2017

TGF(beta) Mediated Structural Remodeling Facilitates Optic Fissure Fusion And The Necessity Of BMP Antagonism In This Process

The optic fissure is a transient gap in the developing vertebrate eye, which must be closed as development proceeds. A persisting optic fissure, coloboma, is a major cause for blindness in children. Multiple factors are genetically linked to coloboma formation. However, especially the process of optic fissure fusion is still largely elusive on a cellular and molecular basis.\n\nWe found a coloboma phenotype in mice with a targeted inactivation of the transforming growth factor 2 (TGF{beta}2). Here the optic fissure margins got in touch, however, failed to fuse. Transcriptomic analyses indicated TGF{beta} mediated ECM remodeling during optic fissure fusion. For functional analyses, we switched model systems and made use of zebrafish. We found TGF{beta} ligands expressed in the developing zebrafish eye, and the ligand binding receptor in the optic fissure. Using a new in vivo TGF{beta} signaling reporter, we also found active TGF{beta} signaling in the margins of the optic fissure. We addressed the function of Cadherin 6 (cdh6), one of the TGF{beta} regulated genes, by knock down experiments in zebrafish and found a prominent coloboma phenotype. Cdh6 was often found involved in processes of epithelial to mesenchymal transition (EMT), strengthening our hypothesis that an EMT-like process is also necessary for optic fissure fusion. Furthermore, we found Gremlin 2b (grem2b) and Follistatin a (fsta), homologs of TGF{beta} regulated bone morphogenetic protein (BMP) antagonists, expressed in the optic fissure margins, indicating the necessity of a localized inhibition of BMP signaling. Finally, we show that induced BMP expression is sufficient to inhibit optic fissure fusion. Together with our previous findings this indicates a dual role of BMP signaling during optic fissure closure.\n\nSummary statementTGF{beta} is crucial for optic fissure fusion, involving cdh6. TGF{beta} mediated optic fissure fusion is potentially hampered by BMP signaling, which is blocked by TGF{beta} induced BMP antagonists within the optic fissure margins.

developmental biology↗