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Maintenance of Melanocyte Stem Cell Quiescence by GABA-A Signaling in Larval

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Maintenance of Melanocyte Stem Cell Quiescence by GABA-A Signaling in Larval Genetics: Early Online, published on August 23, 2019 as 10.1534/genetics.119.302416 1 1 Maintenance of melanocyte stem cell quiescence by GABA-A signaling in larval 2 zebrafish 3 4 James R. Allen1*, James B. Skeath1, Stephen L. Johnson1† 5 6 1Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, 7 63110, USA 8 9 *Corresponding Author 10 † Deceased 11 Dedication: This paper is dedicated to the late Dr. Stephen L. Johnson. 12 13 14 15 16 17 18 19 20 21 22 23 Copyright 2019. 2 1 2 3 Running Title: GABA-A inhibits zebrafish pigmentation 4 Key Words: GABA, melanocyte, GABA-A receptors, quiescence, zebrafish, 5 pigmentation, inhibition, CRISPR 6 Corresponding Author: 7 Department of Genetics, Room 6315 Scott McKinley Research Building, 4523 Clayton 8 Avenue, Washington University School of Medicine, St. Louis, MO, 63110 9 Ph: 314-362-05351, E-mail: [email protected] 10 11 12 13 14 15 16 17 18 19 20 21 22 23 3 1 Abstract: 2 In larval zebrafish, melanocyte stem cells (MSCs) are quiescent, but can be recruited to 3 regenerate the larval pigment pattern following melanocyte ablation. Through 4 pharmacological experiments, we found that inhibition of GABA-A receptor function, 5 specifically the GABA-A rho subtype, induces excessive melanocyte production in larval 6 zebrafish. Conversely, pharmacological activation of GABA-A inhibited melanocyte 7 regeneration. We used CRISPR-Cas9 to generate two mutant alleles of gabrr1, a subtype 8 of GABA-A receptors. Both alleles exhibited robust melanocyte overproduction, while 9 conditional overexpression of gabrr1 inhibited larval melanocyte regeneration. Our data 10 suggest that gabrr1 signaling is necessary to maintain MSC quiescence and sufficient to 11 reduce, but not eliminate, melanocyte regeneration in larval zebrafish. 12 13 Introduction: 14 Vertebrate animals often rely on undifferentiated precursors to regulate growth and 15 homeostasis of specific tissues. These precursors, adult stem cells (ASCs), undergo long- 16 term self-renewal throughout the lifetime of the organism to maintain the growth and 17 regenerative potential of their target tissue. ASCs are found in many tissues including 18 blood, muscle, skin, and nervous system (Bertrand, Kim et al. 2007, Cheung and Rando 19 2013, Nishimura, Jordan et al. 2002, Ma, Bonaguidi et al. 2009). While some ASCs 20 continually proliferate to maintain their target tissue, others remain quiescent or dormant 21 and must be recruited in order to enter a proliferative state, often induced by depletion of 22 differentiated cells in their respective tissues (Li and Bhatia 2011). Understanding the 4 1 pathways that maintain ASC quiescence and that recruit quiescent ASCs to proliferate is 2 critical to elucidate vertebrate tissue growth and homeostasis. 3 4 Zebrafish pigmentation, specifically melanocyte development, is an excellent model 5 system to dissect the genetic and molecular basis of ASC quiescence and recruitment. 6 Both adult melanocytes and melanocytes that regenerate appear to derive from 7 recruitable melanocyte stem cells (MSCs) (Johnson, Africa et al. 1995, Rawls and 8 Johnson 2000). For example, genetic studies indicate that the embryonic melanocyte 9 pattern develops from direct-developing melanocytes and is complete by 3 days post 10 fertilization (dpf) (Hultman, Budi et al. 2009). Under normal conditions, few new 11 melanocytes develop from 3 dpf until the onset of metamorphosis at approximately 15 dpf 12 (Hultman and Johnson 2010). However, when embryonic melanocytes are removed via 13 laser or chemical treatment during this time, a rapid and complete regeneration of the 14 melanocyte pattern occurs through activation of cell division in melanocyte precursors, 15 MSCs (Yang, Sengelmann et al. 2004, Yang and Johnson 2006). MSCs normally lie 16 dormant during larval zebrafish pigmentation, but can be recruited upon loss of 17 differentiated melanocytes. The pathways that regulate MSC quiescence and recruitment 18 are poorly understood. 19 20 Forward genetic studies have helped clarify the genetic regulatory hierarchy that controls 21 melanocyte production and MSC proliferation in zebrafish. These studies highlight the 22 importance of three genes in zebrafish pigmentation – the receptor tyrosine kinase 23 erbb3b, the transcription factor mitfa, and the receptor tyrosine kinase kita. Adult zebrafish 5 1 mutant for erbb3b, named picasso, exhibit defective melanocyte stripe formation, even 2 though larval erbb3b mutants exhibit a wild-type pigment pattern (Budi, Patterson et al. 3 2008). Critically, when picasso mutant zebrafish are challenged for melanocyte 4 regeneration during larval stages, melanocyte regeneration is completely abrogated, 5 suggesting that regenerating melanocytes require erbb3b function, while early embryonic 6 melanocytes do not (Hultman, Budi et al. 2009). This finding led to a model wherein a 7 subset of migratory neural crest cells directly differentiate into embryonic melanocytes 8 (direct-developing melanocytes), and other erbb3b-dependent neural crest cells establish 9 undifferentiated melanocyte precursors, MSCs, that persist throughout zebrafish adult life 10 and can be recruited to form new (stem-cell derived) melanocytes throughout larval and 11 adult stages (Dooley, Mongera et al. 2013). 12 13 Additional insight into MSCs arose from experiments using a temperature-sensitive 14 mutation of melanocyte inducing transcription factor a (mitfa), which is required for all 15 melanocyte development and survival across vertebrate biology (Lister, Robertson et al. 16 1999, Levy, Khaled et al. 2006). These studies revealed that mitfa function was required 17 for the embryonic pigment pattern, but was not required for the survival of MSCs 18 (Johnson, Nguyen et al. 2011). Therefore, while required for melanocyte survival, mitfa 19 function is not required for the survival of MSCs that can regenerate larval melanocytes 20 and produce the adult pigment pattern. 21 22 The receptor tyrosine kinase kita plays key roles during zebrafish pigment patterning. 23 Removal of kita function, as seen in the sparse mutant, results in a roughly 50% loss of 6 1 larval melanocytes, but the adult melanocyte pattern is largely normal (Parichy, Rawls et 2 al. 1999). Thus, kita function is required for the development of direct developing 3 melanocytes. kita does, however, regulate MSC function. For example, kita function is 4 required for melanocyte regeneration during larval stages and for melanocyte 5 regeneration in the caudal fin at all stages (Rawls and Johnson 2001, Rawls and Johnson 6 2003, O'Reilly-Pol and Johnson 2013). 7 8 GABA is a major inhibitory neurotransmitter that transduces its signal by binding to and 9 activating GABA receptors, such as the GABA-A receptor class (Bormann 2000). GABA- 10 A receptors are voltage-gated chloride channels. When activated, they allow Cl- ions to 11 move down their electrochemical gradient into the cell, which hyperpolarizes the cell and 12 inhibits action potential propagation along axons (Sigel and Steinmann 2012). Although 13 GABA is best known to function as a neurotransmitter, prior studies indicated that GABA 14 can inhibit the proliferation of murine embryonic stem cells and peripheral neural crest 15 stem cells (Young and Bordey 2009, Teng, Tang et al. 2013). A role for GABA signaling 16 in regulating vertebrate pigment patterning, however, has not been shown. 17 18 Here, we show that pharmacological and genetic inhibition of GABA-A receptor function 19 leads to excessive melanocyte production during larval zebrafish development, with the 20 newly produced melanocytes likely arising from MSCs. Conversely, we show that 21 pharmacological or genetic activation of GABA-A signaling inhibits melanocyte 22 regeneration. Our work shows that GABA-mediated signaling promotes MSC quiescence 7 1 during zebrafish development and highlights the importance of membrane potential and 2 bioelectric sensing in regulating pigment patterning in vertebrates. 3 4 Materials and Methods: 5 Zebrafish stocks and husbandry 6 Adult fish were raised and maintained at 14L:10D light-to-dark cycle according to 7 previously standardized protocols (Westerfield 2000). To facilitate melanocyte 8 quantification, homozygous mlpha fish was used as wild-type and all experiments were 9 performed in a homozygous mlpha genetic background unless otherwise indicated 10 (Sheets, Ransom et al. 2007). To perform our melanocyte differentiation assay, we used 11 mlpha fish carrying Tg(fTyrp1:GFP)j900 (Tryon and Johnson 2012). To genetically ablate 12 melanocytes, we used mlpha fish homozygous for the temperature-sensitive mitfavc7 13 mutation (Johnson, Nguyen et al. 2011). The kitab5 allele in a mlpha background was 14 used in the study to test lineage specificity within MSCs (Parichy, Rawls et al. 1999). We 15 used the mlpha background to generate our two CRISPR-based mutations in gabrr1. 16 Embryos of each genotype used in the present study were generated from in vitro 17 fertilization. 18 Pharmacological reagents and drug screening 19 Our initial screen used a drug repurposing panel (Pfizer) containing approximately 500 20 unique compounds to identify melanocyte promoting drugs. In this panel, each compound 21 was supplied as a 30 mM stock solution in 96-well plates. We subsequently diluted each 8 1 compound into 2mM working solutions for further testing across multiple doses generally 2 ranging between 1-100 µM in 96 well plates. With this approach, we identified three 3 compounds that
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