The Function Of M6A Writer KIAA1429 In Astrocytes

m6A is an epigenetic modification of RNA,involved in the post-transcriptional regulation of the genes in eukaryotes.A study showed there is the most abundant content of m6A among various tissues and organs,suggesting RNA methylation may play a critical role in the development or function of the central nervous system（CNS）.The enzymes involved in the m6A methylation,demethylation,and recognition are writers,erasers,and readers protein respectively,and these proteins are generally highly expressed in CNS.Over the past ten years,a series of studies have been carried out on the role and mechanism of m6A and its functional proteins in the CNS,and it has been found that learning and memory,cortical development,and cerebellar function are regulated by m6A modification.However,there is still a lack of detailed research on the functional differences in m6A and its functional proteins among different types of nerve cells,such as neurons and glial cells.The m6A writer KIAA1429,a component of the methyltransferase complex,is still unclear about its physiological function and mechanism in the CNS,especially in different cell types.Moreover,known as the most numerous and important glial cells in CNS（including the brain and retina）,astrocytes are widely involved in the correct execution of retinal and brain functions,which also shows a high-level expression of KIAA1429.So we want to focus on the specific cell types--astrocytes,and explore the physiological function and mechanism of m6A writer KIAA1429 in them.Gfap-Cre and Kiaa1429^fl/fl mice were crossbred to derive our mice model to achieve specific knockout of KIAA1429 in retinal and brain astrocytes,which are used to carry out our research project.Firstly,we observed that the adult conditional knockout（CKO）mice’s eyeballs showed different degrees of constriction,accompanied by other defects such as the disordered structure of the lens,excessively covered iris resulting in small or no pupil,and abnormal corneal stroma.In addition,astrogliosis and reduced density of three-layer retinal vessels plexus were found in adult CKO mice’s retina.Notably,the behavioral tests suggested visual dysfunction in CKO mice to some extent.Through single-cell nuclear transcriptome sequencing of mice retina,we found that Kiaa1429may affect the renewal and injury repair of retinal vessels via the signal pathway of angiogenesis of astrocytes around adulthood.In contrast,we observed a decreased number of brain astrocytes in multiple brain regions in P6～P9 CKO mice,but no significance in abnormal proliferation or apoptosis of astrocytes was detected.Then we next found CKO mice showed more stereotyped behavior--grooming.So,we further assumed that Kiaa1429 may affect the differentiation of radial glial cells during the early postnatal development,resulting in decreased brain astrocytes.Above all,our results suggested that Kiaa1429 may regulate the fate of astrocytes through two distinct pathways and further affect the function of CNS（including retina and brain）.Explaining the regulatory function and mechanism of Kiaa1429-mediated m6A in CNS astrocytes would promote us to improve the functional mechanism of RNA methylation in the CNS,from the angle of different cell types.Beyond that,it is beneficial to understand the pathogenesis of human eye diseases from an epigenetic perspective,such as microphthalmia.