Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain

Victoria L Castro,Nayeli G Reyes-Nava,David Paz,Joel F Reyes,Anita M Quintana

doi:10.1186/s12868-020-00577-1

Victoria L Castro, Nayeli G Reyes-Nava + Show 3 more

Open Access

https://doi.org/10.1186/s12868-020-00577-1

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Journal: BMC Neuroscience	Publication Date: Jun 10, 2020
Citations: 9	License type: open-access

Affiliation: The University of Texas at El Paso

Abstract

BackgroundPrecise regulation of neural precursor cell (NPC) proliferation and differentiation is essential to ensure proper brain development and function. The HCFC1 gene encodes a transcriptional co-factor that regulates cell proliferation, and previous studies suggest that HCFC1 regulates NPC number and differentiation. However, the molecular mechanism underlying these cellular deficits has not been completely characterized.MethodsHere we created a zebrafish harboring mutations in the hcfc1a gene (the hcfc1aco60/+ allele), one ortholog of HCFC1, and utilized immunohistochemistry and RNA-sequencing technology to understand the function of hcfc1a during neural development.ResultsThe hcfc1aco60/+ allele results in an increased number of NPCs and increased expression of neuronal and glial markers. These neural developmental deficits are associated with larval hypomotility and the abnormal expression of asxl1, a polycomb transcription factor, which we identified as a downstream effector of hcfc1a. Inhibition of asxl1 activity and/or expression in larvae harboring the hcfc1aco60/+ allele completely restored the number of NPCs to normal levels.ConclusionCollectively, our data demonstrate that hcfc1a regulates NPC number, NPC proliferation, motor behavior, and brain development.

Highlights

Precise regulation of neural precursor cell (NPC) proliferation and differentiation is essential to ensure proper brain development and function
HCFC1 is highly conserved across species [19] and zebrafish have been used as a model system to understand the mechanisms by which mutations in HCFC1 cause disease [16, 20]
Initial crosses between heterozygous carriers of the hcfc1aco60/+ allele failed to generate homozygous progeny and did not obey Mendelian inheritance patterns. These results indicate that Hcfc1a is required for early development, which is consistent with previously published studies [21, 22], the mechanism for embryonic lethality of the homozygous allele was not explored further here

Summary

Introduction

Precise regulation of neural precursor cell (NPC) proliferation and differentiation is essential to ensure proper brain development and function. Results: The hcfc1aco60/+ allele results in an increased number of NPCs and increased expression of neuronal and glial markers These neural developmental deficits are associated with larval hypomotility and the abnormal expres‐ sion of asxl, a polycomb transcription factor, which we identified as a downstream effector of hcfc1a. Recent evidence suggests that the HCFC1 gene, which encodes a transcriptional cofactor, is essential for stem cell proliferation and metabolism [12, 13] in a variety of different tissue types, including NPCs [14,15,16,17].

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