Cellular expression of Midkine‐a and Midkine‐b during retinal development and photoreceptor regeneration in zebrafish

Abstract

In the retina of adult teleosts, stem cells are sustained in two specialized niches: the ciliary marginal zone (CMZ) and the microenvironment surrounding adult Müller glia. Recently, Müller glia were identified as the regenerative stem cells in the teleost retina. Secreted signaling molecules that regulate neuronal regeneration in the retina are largely unknown. In a microarray screen to discover such factors, we identified midkine-b (mdkb). Midkine is a highly conserved heparin-binding growth factor with numerous biological functions. The zebrafish genome encodes two distinct midkine genes: mdka and mdkb. Here, we describe the cellular expression of mdka and mdkb during retinal development and the initial, proliferative phase of photoreceptor regeneration. The results show that in the embryonic and larval retina mdka and mdkb are expressed in stem cells, retinal progenitors and neurons in distinct patterns that suggest different functions for the two molecules. Following the selective death of photoreceptors in the adult, mdka and mdkb are co-expressed in horizontal cells and proliferating Müller glia and their neurogenic progeny. These data reveal that Mdka and Mdkb are signaling factors present in the retinal stem cell niches in both embryonic and mature retinas, and that their cellular expression is actively modulated during retinal development and regeneration.

Müller glial cell reprogramming and retina regeneration

“…This is probably an underestimate since these studies only interrogated ~60% or less of the zebrafish genome. Nonetheless, this analysis has already facilitated the identification and characterization of a number of regeneration-associated genes that contribute to Müller glia's transition from a fully differentiated support cell to one with stem cell characteristics 10,12,14,63,64,83,84,88,94,96–101 .…”

“…Interestingly, when Müller glia in the uninjured retina are forced to reprogram and generate progenitors, these progenitors have the capacity to make all retinal cell types 63,83,96 . Experimental paradigms that result in damage to particular cell types (such as photoreceptors or bipolar cells) have demonstrated that progenitors can replace the lost cell types 12,14,67,82,101,112–114 . However, because these studies used only antibodies or transgenic reporter lines that detect the damaged cell type, it was not possible to determine if progenitors also made other cell types that were only transiently maintained.…”

Regulated Reprogramming in the Regeneration of Sensory Receptor Cells

“…Although it is not yet known whether the Müller glia are fully reprogrammed to retinal progenitors in fish, several developmentally important genes have been shown to be necessary for successful regeneration; for example, knockdown of the proneural bHLH transcription factor Ascl1a blocks regeneration (Fausett et al, 2008), as does knockdown of proliferating cell nuclear antigen (PCNA) (Thummel et al, 2008). Signaling factors such as Midkine-a and –b, galectin and ciliary neurotrophic factor (CNTF) are up-regulated after injury, and potentially important in the proliferation of the Müller cells that underlies regeneration (Calinescu et al, 2009; Kassen et al, 2009). …”

The Zebrafish Galectin Drgal1-L2 Is Expressed by Proliferating Müller Glia and Photoreceptor Progenitors and Regulates the Regeneration of Rod Photoreceptors

“…Fourth, these data add to the functional roles of galectins in biological systems and expand the list of candidate molecules and signaling pathways expressed in stem and pro- genitor cells during retinal injury and regeneration. 33 Finally, these data add Drgal1-L2 to the molecular signature of Müller glia as they adopt the features of neural stem cells (see also 14,[34][35][36].…”