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PDGF-C Signaling Is Required for Normal Cerebellar Development Sara Gillnäs

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PDGF-C Signaling Is Required for Normal Cerebellar Development Sara Gillnäs PDGF-C signaling is required for normal cerebellar development An analysis of cerebellar malformations in PDGF-C impaired mice Sara Gillnäs Degree project in biology, Master of science (2 years), 2021 Examensarbete i biologi 60 hp till masterexamen, 2021 Biology Education Centre and Department of Immunology, Genetics and Pathology, Dag Hammarskjölds väg 20, 751 85 Uppsala, Sweden, Uppsala University Supervisor: Johanna Andrae External opponent: Linda Fredriksson Table of contents Abstract ……………………………………………………………………………………... 2 List of abbreviations ………………………………………………………………………… 3 1. Introduction …………………………………………………………………………. 4 1.1 Platelet derived growth factors and their receptors ……………………………... 4 1.2 The Pdgfc-/-; PdgfraGFP/+ phenotype …………………………………………….. 4 1.3 Cerebellar development and morphology ………………………………………. 5 1.4 Ependymal development and function ………………………………………….. 6 1.5 Cerebellar germinal zones and patterning ………………………………………. 7 1.6 Expression pattern of PDGF-C and PDGFRɑ …………………………………... 8 1.7 Aim of the study ………………………………………………………………… 8 2. Materials and Methods ……………………………………………………………… 8 2.1 Animals …………………………………………………………………………. 8 2.2 Tissue preparation ………………………………………………………………. 9 2.3 Histology and Immunofluorescence staining ………………………………….... 9 2.4 Quantification and statistical analysis of cerebellar vasculature ………………. 11 2.5 Microscopy and imaging ………………………………………………………. 11 3. Results ……………………………………………………………………………... 11 3.1 Pdgfc-/-; PdgfraGFP/+ mice display abnormal cerebellar development …………. 11 3.2 Ependymal disruption in the ventricular zone of the fourth ventricle …………. 13 3.3 Ectopic expression of rhombic lip derived cells ………………………………. 17 3.4 Cerebellar vascularization in Pdgfc-/-; PdgfraGFP/+ mice …………………….... 18 4. Discussion …………………………………………………………………………. 19 4.1 Limitations of this study ………………………………………………………. 19 4.2 PDGF-C impaired mice resembles human Dandy-Walker malformation …….. 20 4.3 Stretching of the ventricular lining due to abnormal development ……………. 20 4.4 Astrocyte accumulation indicate possible repair mechanism ………………….. 23 4.5 PDGF-C signaling important for migration of rhombic lip late derivatives …... 23 4.6 Vascular bed appears normal in the neonatal Pdgfc-/-; PdgfraGFP/+ cerebellum ..25 Acknowledgements ………………………………………………………………………... 25 References …………………………………………………………………………………. 25 Appendix …………………………………………………………………………………... 29 Uppsala University Sara Gillnäs Abstract Platelet-derived growth factor-C (PDGF-C) and its tyrosine kinase receptor PDGFRɑ have been shown to contribute to several key processes during central nervous system (CNS) development, including normal vascularization and formation of cerebral ventricles and basal membrane of the meninges. Due to redundancy between PDGF-C and PDGF-A, PDGF-C specific roles are sometimes masked and difficult to determine. Using the double mutant Pdgfc-/-;PdgfraGFP/+ mouse (Mus musculus) strain we were able to detect and examine a new, undescribed phenotype of PDGF-C impaired mice, namely cerebellar malformations. These mutant mice displayed an upwards rotation of the cerebellar vermis with a severe posterior vermis hypoplasia and an enlarged fourth ventricle, suggesting PDGF-C/PDGFRɑ signaling as a novel candidate to induce Dandy-Walker malformation (DWM). Due to suspected cerebellar vascular malformation a quantification of diameter, density and number of vessels were performed. A significant increase (P < 0.05) of the number and density of vascular bed in the cerebellar nuclei was detected, however the vessel diameter was not significantly different (P > 0.05) in Pdgfc-/-;PdgfraGFP/+ mice in comparison with the control. Through immunofluorescence staining we detected discontinuation of the ependyma in the acute angle of the ventricular zone adjacent to the rhombic lip, interfacing the fourth ventricle and cerebellar anlagen. We further noted ectopic expression of rhombic lip derived cells in the ventricular zone, suggesting a misguided migration due to ablation of PDGF-C. We conclude that PDGF- C is an essential player in normal cerebellar development. 2 Uppsala University Sara Gillnäs Abbreviation AS - astrocytes CN - Cerebellar nuclei CSF -Cerebrospinal fluid DWM - Dandy-Walker malformation E - Embryonic day EC - Ependymal cells EGZ - External granular zone/layer 4V - Fourth ventricle GCP - Granule cell progenitors IGL - Granular layer IF - Immunofluorescent staining ML - Molecular layer NSC - Neural stem cells P - Postnatal day PCL - Purkinje cell layer PCP - Purkinje cell precursors PDGF-C - Platelet derived growth factor C PDGFRɑ - Platelet derived growth factor receptor alpha r1 - Rhombomere 1 RL - Rhombic lip SVZ - Subventricular zone VZ - Ventricular zone 3 Uppsala University Sara Gillnäs 1. Introduction 1.1 Platelet derived growth factors and their receptors The platelet-derived growth factors (PDGFs) are widely, but specifically, expressed throughout the body. PDGF signaling has a vast importance during several developmental processes including organogenesis, angiogenesis and hematopoiesis (reviewed by Andrae et al. 2008). There are four PDGF ligands (PDGFA, -B, -C and -D) currently known, composed of polypeptide chains. These polypeptide chains form dimers, most commonly homodimers (reviewed by Andrae et al. 2008). However, heterodimerization of PDGF-AB has been seen in in vitro experiments (Ekman et al. 1999). When the ligand binds to the receptor, a tyrosine residue of the intracellular domain of the receptor is autophosphorylated. This activation leads to a downstream cascade in the cell through a multitude of signaling pathways, such as Ras- MAPK, PI3K and PLCγ (reviewed by Heldin & Westermark 1999). In mammalian in vivo studies, a limited number of PDGF-PDGFR interactions has been confirmed, including restricted interaction of PDGF-AA and PDGF-CC to PDGF-receptor-alpha (PDGFRɑ) (reviewed by Andrae et al. 2008). 1.2 The Pdgfc-/-;PdgfraGFP/+ phenotype PDGF-A and PDGF-C both signal though the PDGFRɑ and they have partially redundant functions. To phenocopy (or mimic) the severe phenotype seen in Pdgfrɑ-/- mice, both PDGF- A and PDGF-C need to be knocked out (Pdgfc-/-; Pdgfa-/-) (Ding et al. 2004). To surpass the redundancy of PDGF-A and PDGF-C, we use the double transgenic mouse strain Pdgfc-/-; PdgfraGFP/+ with only one functional locus of the receptor gene; preventing PDGF-A from rescuing the phenotype. We argue Pdgfc-/-; PdgfraGFP/+ mice to be a sufficient model system to facilitate the study the role of PDGF-C as Pdgfc-/- mice doesn’t exhibit several of the pathological phenotypes, including the cerebellar malformation. Furthermore, as Pdgfa-/-; PdgfraGFP/+ mice doesn’t display the cerebellar phenotype we can be sure that the phenotype is due to insufficient PDGF-C/PDGFRɑ signaling. 4 Uppsala University Sara Gillnäs Figure 1. Schematic illustration of cerebellar germinal zones, migration paths and adult morphology in mid-sagittal sections. (A) The main germinal zones during cerebellar development are the rhombic lip (RL) (red area) and the ventricular zone (VZ) (yellow area). From the RL the granule neuron precursors (blue cells) migrate tangentially in a subpial stream (blue arrow), giving rise to the external granular zone/layer (EGZ), while the glutamatergic neurons (red cells), including the cerebellar nuclei neurons, avert radially (red arrow) to reach the cerebellar nuclei (CN) anlagen. The VZ, adjacent to the fourth ventricular (4V), is the source of all GABAergic neurons (yellow cells), such as Purkinje cells. These cells migrate radially (yellow arrow) across the cerebellar anlage, towards the cerebellar cortex. (B) The adult cerebellar grey matter consists of the CN and cortex. The cortex is subdivided into three layers; the molecular layer (ML), Purkinje cell layer (PCL) and internal granular layer (IGL). The anterior vermis, posterior superior vermis and posterior inferior vermis constitute the three cerebellar lobes, which are further subdivided into lobules. A: Anterior, D: Dorsal, V: Ventral, P: Posterior. Pdgfc-/-; PdgfraGFP/+ mice exhibit several severe phenotypes; spina bifida occulta, elongated skull, brain and spine hemorrhaging and lung emphysema (Andrae et al. 2016). Detected malformations in the brain consists of vascular malformations, neuronal over-migration in the cerebral cortex due to deficient formation of the meningeal basal membrane and ventricular malformations including hydrocephalus in rare cases (Andrae et al. 2016; Fredriksson et al. 2012). The severity is variable, but the progression of the disease is rapid and very few mice surpass postnatal day 15 (P15), given a stable genetic background (Andrae et al. 2016). Most mice die a few days after birth. Initial observations of cerebellum indicated an irregular foliation and lobules formation as well as hypoplasia of the posterior vermis (Andrae et al. unpublished). These phenotypes have all been described in the pathological umbrella disorder Dandy-Walker malformation (DWM) (Sasaki-Adams et al. 2008; Parisi & Dobyns 2003). Abnormal cerebellar vascular bed was also suspected (Andrae et al. unpublished). 1.3 Cerebellar development and morphology The cerebellum is divided into two hemispheres with the vermis in between, constituting the midline. During development the mammalian cerebellum first divides into three lobes which 5 Uppsala University Sara Gillnäs are subdivided into ten lobules through further foliation, the lobes are continuous between the vermis and cerebellar hemispheres (Leto et al. 2016; Sudarov & Joyner 2007).
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