biostudies-literatureBosquez Huerta NANICHD NIH HHSNIA NIH HHSFoundation for the National Institutes of HealthNINDS NIH HHS115121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11932065biostudies-literatureUnknown44(1)Astrocytes exhibit diverse cellular and molecular properties across the central nervous system (CNS). Recent studies identified region-specific transcription factors (TF) that oversee these diverse properties; how sex differences intersect with region-specific transcriptional programs to regulate astrocyte function is unknown. Here, we show that the TF Nkx6.1 is specifically expressed in ventral astrocytes of the spinal cord and that its deletion results in sex-specific effects on astrocyte morphology. Astrocytes from males exhibit enhanced morphological complexity, accompanied by increased motor function and cholinergic synapses. In contrast, female astrocytes exhibit reduced complexity and no changes in motor function. Mechanistically, we found that Nkx6.1 exhibits sex-specific DNA-bindiCell reportsSex-specific astrocyte regulation of spinal motor circuits by Nkx6.1.PMC11932065R01 NS110859RF1 AG054111F31 NS124310P50 HD103555R01 AG071687R35 NS132230R01 NS126787Sardar DSert OAkdemir ESChristine Song EARasband MNJo JYu KSanchez KLee ZFCheng YTBosquez Huerta NAMaleki ELee HKDeneen BWoo JHarmanci ASfalseSex-specific astrocyte regulation of spinal motor circuits by Nkx6.1.Astrocytes exhibit diverse cellular and molecular properties across the central nervous system (CNS). Recent studies identified region-specific transcription factors (TF) that oversee these diverse properties; how sex differences intersect with region-specific transcriptional programs to regulate astrocyte function is unknown. Here, we show that the TF Nkx6.1 is specifically expressed in ventral astrocytes of the spinal cord and that its deletion results in sex-specific effects on astrocyte morphology. Astrocytes from males exhibit enhanced morphological complexity, accompanied by increased motor function and cholinergic synapses. In contrast, female astrocytes exhibit reduced complexity and no changes in motor function. Mechanistically, we found that Nkx6.1 exhibits sex-specific DNA-bindi2025-01-01T00:00:00Z2025 Jan2026-06-03T02:36:05.917Z2025-07-09T03:04:43.739ZS-EPMC119320653973173510.1016/j.celrep.2024.115121