Holoprosencephaly with a Special Form of Anophthalmia Result from Experimental Induction of bmp4, Oversaturating BMP Antagonists in Zebrafish.

Vision is likely 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). During normal development, both domains are split and consecutively, two optic vesicles and two telencephalic lobes emerge. If this process is hampered, the domains remain condensed at the midline. The resulting developmental disorder is termed holoprosencephaly (HPE). The typical ocular finding associated with intense forms of HPE is cyclopia. However, also anophthalmia and coloboma can be associated with HPE. Here, we report that a correct balance of Bone morphogenetic proteins (BMPs) and their antagonists are important for forebrain and eye field cleavage. Experimental induction of a BMP ligand results in a severe form of HPE showing anophthalmia. We identified a dysmorphic forebrain containing retinal progenitors, which we termed crypt-oculoid. Optic vesicle evagination is impaired due to a loss of rx3 and, consecutively, of cxcr4a. Our data further suggest that the subduction of prospective hypothalamic cells during neurulation and neural keel formation is affected by the induction of a BMP ligand.

Regulation of electrogenic Na+ /HCO3- cotransporter 1 (NBCe1) function and its dependence on m-TOR mediated phosphorylation of Ser245.

Astrocytes are pivotal responders to alterations of extracellular pH, primarily by regulation of their principal acid-base transporter, the membrane-bound electrogenic Na+ /bicarbonate cotransporter 1 (NBCe1). Here, we describe amammalian target of rapamycin (mTOR)-dependent and NBCe1-mediated astroglial response to extracellular acidosis. Using primary mouse cortical astrocytes, we investigated the effect of long-term extracellular metabolic acidosis on regulation of NBCe1 and elucidated the underlying molecular mechanisms by immunoblotting, biotinylation of surface proteins, intracellular H+ recording using the H+ -sensitive dye 2',7'-bis-(carboxyethyl)-5-(and-6)-carboxyfluorescein, and phosphoproteomic analysis. The results showed significant increase of NBCe1-mediated recovery of intracellular pH from acidification in WT astrocytes, but not in cortical astrocytes from NBCe1-deficient mice. Acidosis-induced upregulation of NBCe1 activity was prevented following inhibition of mTOR signaling by rapamycin. Yet, during acidosis or following exposure of astrocytes to rapamycin, surface protein abundance of NBCe1 remained -unchanged. Mutational analysis in HeLa cells suggested that NBCe1 activity was dependent on phosphorylation state of Ser245 , a residue conserved in all NBCe1 variants. Moreover, phosphorylation state of Ser245 is regulated by mTOR and is inversely correlated with NBCe1 transport activity. Our results identify pSer245 as a novel regulator of NBCe1 functional expression. We propose that context-dependent and mTOR-mediated multisite phosphorylation of serine residues of NBCe1 is likely to be a potent mechanism contributing to the response of astrocytes to acid/base challenges during pathophysiological conditions.

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 as 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.

In Vivo Analysis of Optic Fissure Fusion in Zebrafish: Pioneer Cells, Basal Lamina, Hyaloid Vessels, and How Fissure Fusion is Affected by BMP.

Colobomata, persistent optic fissures, frequently cause congenital blindness. Here, we focused on optic fissure fusion using in vivo time-lapse imaging in zebrafish. We identified the fusion initiating cells, which we termed "pioneer cells." Based on morphology, localization, and downregulation of the neuroretinal (NR) precursor marker rx2, these cells could be considered as retinal pigment epithelial (RPE) progenitors. Notably, pioneer cells regain rx2 expression and integrate into the NR after fusion, indicating that they do not belong to the pool of RPE progenitors, supported by the lack of RPE marker expression in pioneer cells. They establish the first cellular contact between the margins in the proximal fissure region and separate the hyaloid artery and vein. After initiation, the fusion site is progressing distally, increasing the distance between the hyaloid artery and vein. A timed BMP (Bone Morphogenetic Protein) induction, resulting in coloboma, did not alter the morphology of the fissure margins, but it did affect the expression of NR and RPE markers within the margins. In addition, it resulted in a persisting basal lamina and persisting remnants of periocular mesenchyme and hyaloid vasculature within the fissure, supporting the necessity of BMP antagonism within the fissure margins. The hampered fissure fusion had severe effects on the vasculature of the eye.

Functional expression of electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse cortical astrocytes is dependent on S255-257 and regulated by mTOR.

The electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), is the major bicarbonate transporter expressed in astrocytes. It is highly sensitive for bicarbonate and the main regulator of intracellular, extracellular, and synaptic pH, thereby modulating neuronal excitability. However, despite these essential functions, the molecular mechanisms underlying NBCe1-mediated astrocytic response to extracellular pH changes are mostly unknown. Using primary mouse cortical astrocyte cultures, we investigated the effect of long-term extracellular metabolic alkalosis on regulation of NBCe1 and elucidated the underlying molecular mechanisms by immunoblotting, biotinylation of surface proteins, intracellular H+ recording using the H+ -sensitive dye 2',7'-bis-(carboxyethyl)-5-(and-6)-carboxyfluorescein, and phosphoproteomic analysis. The results showed significant downregulation of NBCe1 activity following metabolic alkalosis without influencing protein abundance or surface expression of NBCe1. During alkalosis, the rate of intracellular H+ changes upon challenging NBCe1 was decreased in wild-type astrocytes, but not in cortical astrocytes from NBCe1-deficient mice. Alkalosis-induced decrease of NBCe1 activity was rescued after activation of mTOR signaling. Moreover, mass spectrometry revealed constitutively phosphorylated S255-257 and mutational analysis uncovered these residues being crucial for NBCe1 transport activity. Our results demonstrate a novel mTOR-regulated mechanism by which NBCe1 functional expression is regulated. Such mechanism likely applies not only for NBCe1 in astrocytes, but in epithelial cells as well.

[Neuroanatomy of the Oculomotor System]. / Neuroanatomie des okulomotorischen Systems.

After just a clinical examination, the experienced neurologist can assign specific symptoms quite precisely to distinct lesions within the brain and other parts of the nervous system, on the basis of his neuroanatomical knowledge. This also holds true for lesions affecting the oculomotor system. The aim of this article is to give a comprehensive overview of the neuroanatomical basis of the oculomotor system, in order to facilitate the precise spatial assignment of potential lesions affecting the control of eye movements. After a brief introduction, the components of the system are discussed, including the extraocular muscles and their innervating nerves. The following section will then cover the control of eye movements and will specifically address distinct patterns of eye movements and areas within the central nervous system controlling these. This article also gives a brief overview of the intraocular muscles and their control.

[Neuroanatomy of the Visual Pathway]. / Neuroanatomie der Sehbahn.

Precise knowledge of the neuroanatomy of the visual system including the perception of visual stimuli in the retina, the transmission of visual information to other areas of the central nervous system and the processing of visual information, are most important for diagnostics of diseases, which are affecting this system. Such knowledge allows, even after just a clinical examination, already a quite precise localisation of potential lesions. The aim of this article is to illustrate the neuroanatomy of the visual system with the focus on the visual pathway and the processing of visual information. Next to the main visual pathway, also other retinofugal projections are discussed. Domains, which are important for the oculomotor system, are discussed in another article in this edition of the journal.

BMP7 promotes cardiomyocyte regeneration in zebrafish and adult mice.

Zebrafish have a lifelong cardiac regenerative ability after damage, whereas mammals lose this capacity during early postnatal development. This study investigated whether the declining expression of growth factors during postnatal mammalian development contributes to the decrease of cardiomyocyte regenerative potential. Besides confirming the proliferative ability of neuregulin 1 (NRG1), interleukin (IL)1b, receptor activator of nuclear factor kappa-Β ligand (RANKL), insulin growth factor (IGF)2, and IL6, we identified other potential pro-regenerative factors, with BMP7 exhibiting the most pronounced efficacy. Bmp7 knockdown in neonatal mouse cardiomyocytes and loss-of-function in adult zebrafish during cardiac regeneration reduced cardiomyocyte proliferation, indicating that Bmp7 is crucial in the regenerative stages of mouse and zebrafish hearts. Conversely, bmp7 overexpression in regenerating zebrafish or administration at post-mitotic juvenile and adult mouse stages, in vitro and in vivo following myocardial infarction, enhanced cardiomyocyte cycling. Mechanistically, BMP7 stimulated proliferation through BMPR1A/ACVR1 and ACVR2A/BMPR2 receptors and downstream SMAD5, ERK, and AKT signaling. Overall, BMP7 administration is a promising strategy for heart regeneration.

Glia cell line-derived neurotrophic factor mediates survival of murine sympathetic precursors.

During embryonic development, neurons are first produced in excess, and final numbers are adjusted by apoptosis at later stages. Crucial to this end is the amount of target-derived growth factor available for the neurons. By this means, the target size correctly matches the innervating neuron number. This target-derived survival has been well studied for sympathetic neurons, and nerve growth factor (NGF) was identified to be the crucial factor for maintaining sympathetic neurons at late embryonic and early postnatal stages, with a virtual complete loss of sympathetic neurons in NGF knockout (KO) mice. This indicates that all sympathetic neurons are dependent on NGF. However, also different glia cell line-derived neurotrophic factor (GDNF) KO mice consistently presented a loss of sympathetic neurons. This was the rationale for investigating the role of GDNF for sympathetic precursor/neuron survival. Here we show that GDNF is capable of promoting survival of 30% sympathetic precursors dissociated at E13. This is in line with data from GDNF KOs in which a comparable sympathetic neuron loss was observed at late embryonic stages, although the onset of the phenotype was unclear. We further present data showing that GDNF ligand and canonical receptors are expressed in sympathetic neurons especially at embryonic stages, raising the possibility of an autocrine/paracrine GDNF action. Finally, we show that GDNF also maintained neonatal sympathetic neurons (40%) cultured for 2 days. However, the GDNF responsiveness was lost at 5 days in vitro.

The chemicals between us-First results of the cluster analyses on anatomy embalming procedures in the German-speaking countries.

Hands-on courses utilizing preserved human tissues for educational training offer an important pathway to acquire basic anatomical knowledge. Owing to the reevaluation of formaldehyde limits by the European Commission, a joint approach was chosen by the German-speaking anatomies in Europe (Germany, Austria, Switzerland) to find commonalities among embalming protocols and infrastructure. A survey comprising 537 items was circulated to all anatomies in German-speaking Europe. Clusters were established for "ethanol"-, formaldehyde-based ("FA"), and "other" embalming procedures, depending on the chemicals considered the most relevant for each protocol. The logistical framework, volumes of chemicals, and infrastructure were found to be highly diverse between the groups and protocols. Formaldehyde quantities deployed per annum were three-fold higher in the "FA" (223 L/a) compared to the "ethanol" (71.0 L/a) group, but not for "other" (97.8 L/a), though the volumes injected per body were similar. "FA" was strongly related to table-borne air ventilation and total fixative volumes ≤1000 L. "Ethanol" was strongly related to total fixative volumes >1000 L, ceiling- and floor-borne air ventilation, and explosion-proof facilities. Air ventilation was found to be installed symmetrically in the mortuary and dissection facilities. Certain predictors exist for the interplay between the embalming used in a given infrastructure and technical measures. The here-established cluster analysis may serve as decision supportive tool when considering altering embalming protocols or establishing joint protocols between institutions, following a best practice approach to cater toward best-suited tissue characteristics for educational purposes, while simultaneously addressing future demands on exposure limits.

Schwann cells migrate along axons in the absence of GDNF signaling.

BACKGROUND: During development neural crest derived Schwann Cell (SC) precursors migrate to nerve trunks and populate nascent nerves. Axonal ensheathment by SC is a prerequisite for normal nerve function and the integrity of myelinated as well as nonmyelinated axons. To provide adequate support functions, SC colonize entire nerves. One important prerequisite for this is their migration into distal axonal regions. RESULTS: Here, we studied the role of Glial cell line derived neurotrophic factor (GDNF), a TGF-beta related growth factor, for SC migration. To this end we used a superior cervical ganglion (SCG) explant-SC migration assay, GDNF null mutant mouse embryos and a chemical inhibitor for GDNF signaling in combination with time-lapse imaging. We found that GDNF signaling is dispensable for SC migration along murine embryonic sympathetic axons. Furthermore, in vivo analyzes revealed that SC migration along the sciatic nerve is also not dependent on GDNF. CONCLUSIONS: In contrast to previous in vitro findings in the sciatic nerve and a SC precursor cell line, our results clearly indicate that GDNF is dispensable for embryonic SC migration. This is demonstrated for the sympathetic nervous system and also for the sciatic nerve in mouse.

Interprofessional education in medical and physiotherapy studies for future collaboration.

BACKGROUND: Interprofessional education (IPE) for medical and healthcare professions is highly relevant. It increases knowledge and skills, but also helps to foster the development of collaboration, which is essential for optimal patient care. One important aspect of IPE is to better understand profession's individual attitudes and perceptions towards interprofessionalism and the expected roles and skills for future collaboration in the context of patient care. METHODS: We offered IPE workshops using a peer assisted learning approach, with the focus on anatomy in the area of the lower back and hip. The workshops were attended by medical and physiotherapy students and consisted of three consecutive training sessions with the topics anatomical prosections, anatomy in vivo and orthopedics testing. We focused on student's attitudes and perceptions regarding the relevance of IPE and their expected skills in interprofessionalism. An established questionnaire was used as an instrument for self-assessment before and after the interprofessional experience. To evaluate for significance, analysis was carried out for all groups on pre- and post-course item mean differences. RESULTS: Pre-post score comparison for all groups combined demonstrated significant increase in terms of perceptions and attitudes for several items related to interprofessionalism and interprofessional skills. Medical and physiotherapy students rated themselves significantly higher for different questionnaire items. Students, who had obtained a professional qualification prior to their current studies, rated themselves significantly higher on certain items compared to those who had not. CONCLUSIONS: The results from this brief interprofessional anatomy experience are encouraging. The course led to meaningful improvements in competencies that are highly relevant for effective interprofessional collaboration in the future. Furthermore, identification of differences in professional group perceptions can be useful for development of future IPE workshops.

Microglia promote colonization of brain tissue by breast cancer cells in a Wnt-dependent way.

Although there is increasing evidence that blood-derived macrophages support tumor progression, it is still unclear whether specialized resident macrophages, such as brain microglia, also play a prominent role in metastasis formation. Here, we show that microglia enhance invasion and colonization of brain tissue by breast cancer cells, serving both as active transporters and guiding rails. This is antagonized by inactivation of microglia as well as by the Wnt inhibitor Dickkopf-2. Proinvasive microglia demonstrate altered morphology, but neither upregulation of M2-like cytokines nor differential gene expression. Bacterial lipopolysacharide shifts tumor-educated microglia into a classical M1 phenotype, reduces their proinvasive function, and unmasks inflammatory and Wnt signaling as the most strongly regulated pathways. Histological findings in human brain metastases underline the significance of these results. In conclusion, microglia are critical for the successful colonization of the brain by epithelial cancer cells, suggesting inhibition of proinvasive microglia as a promising antimetastatic strategy.

TGF-beta 1 enhances neurite outgrowth via regulation of proteasome function and EFABP.

Malfunction of the ubiquitin-proteasome system has been implicated as a causal factor in the pathogenesis of aggregation-related disorders, e.g. Parkinson's disease. We show here that Transforming growth factor-beta 1 (TGF-beta), a multifunctional cytokine and trophic factor for dopaminergic (DAergic) neurons modulates proteasome function in primary midbrain neurons. TGF-beta differentially inhibited proteasomal subactivities with a most pronounced time-dependent inhibition of the peptidyl-glutamyl peptide hydrolyzing-like and chymotrypsin-like subactivity. Regulation of proteasomal activity could be specifically quantified in the DAergic subpopulation. Protein blot analysis revealed an accumulation of ubiquitinated proteins after TGF-beta treatment. The identity of these enriched proteins was further analyzed by 2D-gel electrophoresis and mass spectrometry. We found epidermal fatty acid binding protein (EFABP) to be strongly increased and ubiquitinated after TGF-beta treatment and confirmed this finding by co-immunoprecipitation. While application of TGF-beta increased neurite regeneration in a scratch lesion model, downregulation of EFABP by siRNA significantly decreased this effect. We thus postulate that a differential regulation of proteasomal function, as demonstrated for TGF-beta, can result in an enrichment of proteins, such as EFABP, that mediate physiological functions, such as neurite regeneration.

Aged Tgfbeta2/Gdnf double-heterozygous mice show no morphological and functional alterations in the nigrostriatal system.

Loss of dopaminergic neurons in the substantia nigra pars compacta and the resulting decrease in striatal dopamine levels are the hallmarks of Parkinson's disease. Tgfbeta and Gdnf have been identified as neurotrophic factors for dopaminergic midbrain neurons in vivo and in vitro. Haploinsufficiency for either Tgfbeta or Gdnf led to dopaminergic deficits. In this study we therefore analyzed the nigrostriatal system of aged Tgfbeta2 (+/-)/Gdnf (+/-) double-heterozygous mice. Unexpectedly, we found no morphological changes in the nigrostriatal system as compared with age-matched wild-type mice. There were no significant differences in the number of TH-positive midbrain neurons and no changes in the optical density of TH immunoreactivity in striata of Tgfbeta2 (+/-)/Gdnf (+/-) double-heterozygous mice. Moreover, we found no significant differences in the striatal levels of dopamine and its metabolites dihydroxyphenylacetic acid and homovanillic acid. Our results indicate that a combined haploinsufficiency for Tgfbeta2 and Gdnf has no impact on the function and the survival of midbrain DA neurons under normal aging conditions.

An interprofessional teaching approach for medical and physical therapy students to learn functional anatomy and clinical examination of the lower spine and hip.

INTRODUCTION: Pain of the lower back is a frequent symptom and is treated by different health professions. Anatomical as well as clinical knowledge is utmost important for all professions involved in this field. Here, we present a model that brings together an interprofessional team of experts to teach functional and clinical anatomy of the lower spine and hip area to medical and physical therapy students. METHODS: Two groups of medical students (n=60) and physical therapy students (n=77) were designated to two interprofessional clusters, with each cluster of students participating in three workshops, each lasting 40min. Workshops were guided by university anatomists, an orthopedic physician and physical therapists, and each provided specialized training, such as the conduction of clinical, orthopedic functional tests, the identification and palpation of anatomical structures and demonstrations of human anatomical joint prosections. A questionnaire, consisting of 18 questions regarding subjective anatomical and clinical knowledge and application of clinical assessment techniques was used as the evaluation tool before and after participation in the course. Furthermore, the amount of knowledge gained from peer group participants from the other profession versus the knowledge gained from the instructors was assessed. Descriptive statistics of data as well as quantitative data analysis was carried out for pre-post analysis. RESULTS: A total of 148 students participated in the pre-course evaluation and self-assessment and 113 students completed the post-course evaluation and self-assessment. 11 of the students, who completed the pre-course evaluation, and five students who completed the post-course evaluation failed to reveal their affiliation and these were only included in the general and corresponding cluster analysis. A final 132 pre-questionnaire and 97 post-questionnaire results were included in the analyses due to a likely group response bias. Scores for all combined groups showed an increase in the pre-post evaluation of 11.7% (P<.001). Cluster 1 and 2 (pre-post) score comparisons showed an increase of 13.7% (P<.001) and 8.8% (P<.001) respectively. A subgroup pre-post-questionnaire analysis demonstrated that medical students from both clusters had the highest increase in scores (17.6% and 19.9%) in comparison to their physical therapy counterparts (9.1% and 5.8%) (P<.001). Specifically, medical students profited highly from the anatomy in vivo (palpation) as well as clinical, orthopedic assessment exercises. Sub-question analyses showed that students learned from each other as well as from an interprofessional team of guiding experts/instructors, though mostly from the latter. CONCLUSIONS: This course offers an appropriate and effective model that brings together an interprofessional team of experts to teach functional and clinical anatomy to medical and physical therapy students. Study results demonstrated an increase in subject-specific competencies in functional and clinical anatomy of the lower spine and hip. Medical students demonstrated the highest increase in subjective knowledge, especially in regard to clinical examination and assessment, which highlights the usefulness of this course early in the medical education. All students learned from the exchange with interprofessional group members as well as the instructors.

Transforming growth factor beta cooperates with persephin for dopaminergic phenotype induction.

The aim of the present study was to investigate the putative cooperative effects of transforming growth factor beta (TGF-beta) and glial cell line-derived neurotrophic factor (GDNF) family ligands in the differentiation of midbrain progenitors toward a dopaminergic phenotype. Therefore, a mouse midbrain embryonic day (E) 12 neurospheres culture was used as an experimental model. We show that neurturin and persephin (PSPN), but not GDNF, are capable of transient induction of dopaminergic neurons in vitro. This process, however, requires the presence of endogenous TGF-beta. In contrast, after 8 days in vitro GDNF rescued the TGF-beta neutralization-dependent loss of the TH-positive cells. In vivo, at E14.5, no apparent phenotype concerning dopaminergic neurons was observed in Tgf-beta2(-/-)/gdnf(-/-) double mutant mice. In vitro, combined TGF-beta/PSPN treatment achieved a yield of approximately 20% TH-positive cells that were less vulnerable against 1-methyl-4-phenyl pyridinium ion toxicity. The underlying TGF-beta/PSPN differentiation signaling is receptor-mediated, involving p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways. These results indicate that phenotype induction and survival of fully differentiated neurons are accomplished through distinct pathways and individual factor requirement. TGF-beta is required for the induction of dopaminergic neurons, whereas GDNF is required for regulating and/or maintaining a differentiated neuronal phenotype. Moreover, this study suggests that the combination of TGF-beta with PSPN is a potent inductive cocktail for the generation of dopaminergic neurons that should be considered in tissue engineering and cell replacement therapies for Parkinson's disease.

In vivo requirement of TGF-beta/GDNF cooperativity in mouse development: focus on the neurotrophic hypothesis.

Neurotrophic factors are well-recognized extracellular signaling molecules that regulate neuron development including neurite growth, survival and maturation of neuronal phenotypes in the central and peripheral nervous system. Previous studies have suggested that TGF-beta plays a key role in the regulation of neuron survival and death and potentiates the neurotrophic activity of several neurotrophic factors, most strikingly of GDNF. To test the physiological relevance of this finding, TGF-beta2/GDNF double mutant (d-ko) mice were generated. Double mutant mice die at birth like single mutants due to kidney agenesis (GDNF-/-) and congential cyanosis (TGF-beta2-/-), respectively. To test for the in vivo relevance of TGF-beta2/GDNF cooperativity to regulate neuron survival, mesencephalic dopaminergic neurons, lumbar motoneurons, as well as neurons of the lumbar dorsal root ganglion and the superior cervical ganglion were investigated. No loss of mesencephalic dopaminergic neurons was observed in double mutant mice at E18.5. A partial reduction in neuron numbers was observed in lumbar motoneurons, sensory and sympathetic neurons in GDNF single mutants, which was further reduced in TGF-beta2/GDNF double mutant mice at E18.5. However, TGF-beta2 single mutant mice showed no loss of neurons. These data point towards a cooperative role of TGF-beta2 and GDNF with regard to promotion of survival within the peripheral motor and sensory systems investigated.

Morphogenesis and axis specification occur in parallel during optic cup and optic fissure formation, differentially modulated by BMP and Wnt.

Optic cup morphogenesis is an intricate process. Especially, the formation of the optic fissure is not well understood. Persisting optic fissures, termed coloboma, are frequent causes for congenital blindness. Even though the defective fusion of the fissure margins is the most acknowledged reason for coloboma, highly variable morphologies of coloboma phenotypes argue for a diverse set of underlying pathomechanisms. Here, we investigate optic fissure morphogenesis in zebrafish to identify potential morphogenetic defects resulting in coloboma. We show that the formation of the optic fissure depends on tissue flow movements, integrated into the bilateral distal epithelial flow forming the optic cup. On the temporal side, the distal flow translates into a ventral perpendicular flow, shaping the temporal fissure margin. On the nasal side, however, the distal flow is complemented by tissue derived from the optic stalk, shaping the nasal fissure margin. Notably, a distinct population of TGFß-signalling positive cells is translocated from the optic stalk into both fissure margins. Furthermore, we show that induced BMP signalling as well as Wnt-signalling inhibition result in morphogenetic defects of the optic fissure. Our data also indicate that morphogenesis is crucial for a proper positioning of pre-specified dorsal-ventral optic cup domains.