Sex-specific astrocyte regulation of spinal motor circuits by Nkx6.1

Navish A Bosquez Huerta; Zhung-Fu Lee; Eun-Ah Christine Song; Junsung Woo; Yi-Ting Cheng; Debosmita Sardar; Ozlem Sert; Ehson Maleki; Kwanha Yu; Ekin Su Akdemir; Kaitlyn Sanchez; Juyeon Jo; Matthew N Rasband; Hyun Kyoung Lee; Akdes Serin Harmanci; Benjamin Deneen

doi:10.1016/j.celrep.2024.115121

Sex-specific astrocyte regulation of spinal motor circuits by Nkx6.1

Cell Rep. 2024 Dec 27;44(1):115121. doi: 10.1016/j.celrep.2024.115121. Online ahead of print.

Authors

Navish A Bosquez Huerta¹, Zhung-Fu Lee¹, Eun-Ah Christine Song², Junsung Woo², Yi-Ting Cheng³, Debosmita Sardar², Ozlem Sert⁴, Ehson Maleki⁵, Kwanha Yu⁶, Ekin Su Akdemir⁷, Kaitlyn Sanchez², Juyeon Jo⁸, Matthew N Rasband⁹, Hyun Kyoung Lee¹⁰, Akdes Serin Harmanci¹¹, Benjamin Deneen¹²

Affiliations

¹ Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Program in Development, Disease, Models, and Therapeutics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
² Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
³ Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
⁶ Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
⁸ Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
⁹ Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Program in Development, Disease, Models, and Therapeutics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁰ Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Program in Development, Disease, Models, and Therapeutics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
¹¹ Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
¹² Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Program in Development, Disease, Models, and Therapeutics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].

PMID: 39731735
DOI: 10.1016/j.celrep.2024.115121

Abstract

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-binding properties and epigenomic remodeling, identifying Semaphorin 4A (Sema4A) and Gabbr1 as targets regulating astrocyte morphology and cholinergic synapse formation. Collectively, our studies identify astrocytic Nkx6.1 as a key regulator of astrocyte properties in the spinal cord while adding sexual dimorphism as a layer of transcriptional regulation to astrocyte function and circuit activity.

Keywords: Astrocyte; CP: Neuroscience; astrocyte morphology; developmental patterning; motor circuits; sex differences.