rs9556979 — STK24 HPA Axis Regulation

STK24 and the Hippocampal Stress Circuit

Your brain's response to stress depends on a continuous supply of new neurons in the hippocampus — a process called adult hippocampal neurogenesis. This region serves double duty: it encodes memory and, critically, it provides inhibitory control over the HPA axis¹¹ HPA axis
The hypothalamic-pituitary-adrenal axis: the hormonal cascade where the hypothalamus signals the pituitary, which signals the adrenal glands to release cortisol. Healthy hippocampal neurogenesis helps shut this response off. The gene STK24 — encoding a kinase called MST3 — turns out to be essential for keeping that factory running. Variants near STK24, including rs9556979, may influence how well the hippocampus maintains its stress-dampening capacity.

STK24 belongs to the germinal center kinase-III (GCK-III) subfamily of Ste20-related kinases. Unlike most brain-relevant genes that encode neurotransmitter receptors or ion channels, STK24 encodes a master regulator of brain architecture itself — controlling how neurons move into position, grow their dendrites, and form synapses during development and throughout life.

The Mechanism

The rs9556979 variant sits approximately 12 kilobases downstream of the STK24 gene, in a region classified as regulatory. Variants in this position can alter promoter activity, enhancer function, or transcription factor binding that fine-tunes STK24 expression in neural tissue.

Inside neurons, STK24/MST3 operates through at least two critical pathways. First, it regulates neuronal migration²² neuronal migration
The developmental process by which newly born neurons travel from their birthplace in the ventricular zone to their final position in the cortical layers. Correct positioning is essential for functional circuit formation. Tang et al. 2014³³ Tang et al. 2014
Tang J et al. Cdk5-dependent Mst3 phosphorylation and activity regulate neuronal migration through RhoA inhibition. J Neurosci, 2014 showed that MST3 is activated by Cdk5 phosphorylation at Ser79, then phosphorylates RhoA at Ser26 to suppress its GTPase activity — releasing the cytoskeletal brake that allows neurons to extend a leading process and migrate. Silencing Mst3 in developing mouse cortex trapped neurons in a disorganized multipolar state, unable to complete their journey.

Second, in mature neurons, MST3 promotes dendritic spine and synapse formation. Ultanir et al. 2014⁴⁴ Ultanir et al. 2014
Ultanir SK et al. MST3 kinase phosphorylates TAO1/2 to enable Myosin Va function in promoting spine synapse development. Neuron, 2014 found that MST3 phosphorylates TAO1/2 kinases, which direct the motor protein Myosin Va to dendritic spines. Depleting MST3 reduced spine density in hippocampal cultures and in intact layer 2/3 pyramidal neurons.

The 2025 animal model study provides the clearest link to mood and stress. Wu et al. 2025⁵⁵ Wu et al. 2025
Wu KY et al. Stk24 deficiency causes disrupted hippocampal neurogenesis and anxiety-like behavior in mice. Commun Biol, 2025 generated brain-specific Stk24 conditional knockout mice and found that deleting the gene reduced the number of TBR2+, NeuroD+, and DCX+ cells (markers of newborn neurons at successive stages of maturation) and NeuN+/BrdU+ co-labeled mature new neurons in the dentate gyrus. Under stress, these mice had significantly higher plasma corticosterone and greater c-FOS+ neuronal activation than wild-type controls, with upregulated CRH expression — a signature of impaired hippocampal inhibition of the HPA axis. Behaviorally, knockout mice spent more time in exposed areas (center of open field, light compartment of light-dark box), consistent with anxiety-like disinhibition.

The Evidence

Human genetic evidence for STK24's role in anxiety comes from two sources. A genome-wide study of psycho-emotional well-being in 30,063 Russians⁶⁶ 30,063 Russians
Yakovchik AY et al. Genetics of psycho-emotional well-being: genome-wide association study and polygenic risk score analysis. Front Psychiatry, 2024 identified rs9517326 — a neighboring STK24 variant — as significantly associated with HADS-A anxiety scores alongside PTPRN2 and DLGAP4, genes involved in excitatory neurotransmission. The study highlighted STK24's role in neurogenesis and synaptic function as the mechanistic basis.

At the population scale, the largest anxiety GWAS to date — Strom, Levey et al. 2024⁷⁷ Strom, Levey et al. 2024
Strom NI, Levey DF et al. Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling. medRxiv, 2024 — identified 58 loci for major anxiety disorders and underscored the role of genes affecting synaptic biology and neurogenesis. GWAS catalog data show rs9556979 is also associated with body shape measurements (p=3×10⁻¹⁰) and metabolic syndrome (p=1×10⁻¹⁴) — consistent with STK24's broader roles in stress physiology and the brain-metabolic axis.

Practical Implications

The evidence positions STK24 rs9556979 as a moderator of hippocampal resilience under stress. G allele carriers may have reduced STK24 expression in neural tissue, leading to modestly impaired adult hippocampal neurogenesis and a slightly less efficient brake on the HPA stress axis. The practical consequence is a stress response that tends to run somewhat longer and stronger — not a psychiatric diagnosis, but a biological predisposition worth knowing.

Interventions that directly stimulate hippocampal neurogenesis are relevant here: aerobic exercise is the most robustly validated, increasing BDNF and new neuron production within 4-6 weeks of consistent training. Dietary approaches that support BDNF (adequate omega-3 EPA/DHA, sufficient zinc and magnesium) and reduce neuroinflammation may also support hippocampal neurogenesis capacity.

Interactions

rs9556979 and FKBP5 rs1360780 operate through overlapping HPA axis pathways — STK24 affecting the neurogenic brake on cortisol release, and FKBP5 affecting the glucocorticoid receptor feedback loop. Carriers of risk alleles at both loci would be expected to show additive impairment in stress resolution.

BDNF rs6265 (Val66Met) is also relevant: since STK24 supports the structural substrate for hippocampal neurogenesis and BDNF provides the survival signal for new neurons, carriers of both the G allele at rs9556979 and the Met allele at rs6265 may have compounded reduction in adult neurogenesis capacity.