ACVR1C/ALK7: A key member of the TGF-β superfamily

• Gene Information: ACVR1C (activin A receptor type 1C), also known as ALK7, encodes a member of the TGF-β superfamily of type I receptors. The receptor comprises an extracellular ligand-binding domain, a single transmembrane helix, and intracellular GS and kinase domains.
•  Protein Expression: ALK7 is highly abundant in both white and brown adipose tissues, where it regulates lipid storage and energy homeostasis.
• Signaling Pathway: ACVR1C signaling operates through two parallel mechanisms: it primarily activates the canonical Smad2/3-mediated TGF-β pathway, while concurrently triggering non-canonical cascades (including the MAPK and PI3K/AKT pathways) under specific cellular conditions. This dual action allows for the integrated regulation of cellular proliferation, differentiation, migration, and metabolism.
• Therapeutic Inhibition: Therapeutics such as ARO-ALK7 utilize RNA interference (RNAi) to selectively silence the ACVR1C gene. By disrupting the expression of the ACVR1C receptor, this approach effectively reduces visceral adiposity while preserving lean muscle mass.

ALK7

• A region spanning from exon 2 to exon 9 of the mouse Alk7 gene, including the 3' UTR, was replaced with a P2A sequence and the full human ALK7 coding sequence (CDS), including the human ALK7 3' UTR, in B-hALK7 mice.
•  The endogenous mouse promoter and 5' UTR regions were retained. Human ALK7 expression is driven by the endogenous mouse Alk7 promoter, while endogenous mouse Alk7 transcription and translation are disrupted.

Strain-specific analysis of ALK7 mRNA expression in wild-type C57BL/6JNifdc mice and ALK7 humanized mice was performed by RT-PCR. Subcutaneous fat RNA was isolated from wild-type C57BL/6JNifdc mice (+/+) and homozygous ALK7 humanized mice (H/H). cDNA libraries were synthesized by reverse transcription, followed by RT-qPCR using human ALK7-specific primers. Human ALK7 mRNA was detectable in ALK7 humanized mice but not in wild-type mice. Human sequences were further confirmed by Sanger sequencing.

Strain-specific ALK7 mRNA expression analysis in wild-type C57BL/6JNifdc mice and homozygous B-hALK7 mice by RT-qPCR. RNA was isolated from the perirenal fat, perigonadal fat, inguinal subcutaneous fat, and brown fat of wild-type C57BL/6JNifdc mice (+/+) and homozygous B-hALK7 mice (H/H). cDNA was synthesized by reverse transcription, followed by RT-qPCR using primers designed to detect human ALK7 and mouse Alk7 transcripts. Human ALK7 mRNA was exclusively detectable in B-hALK7 mice, but not in wild-type mice.

The inhibitory efficiency of the nucleic acid drugs against human ALK7 in heterozygous B-hALK7 mice. B-hALK7 mice (H/+) were randomly divided into two groups (male, 10 weeks old, n = 5). The human ALK7 targeted nucleic acid drugs (synthesized according to patents), and PBS were administered to the mice individually. The nucleic acid drug was administered in the form of a PBS aqueous solution. The mice were sacrificed on day 14, and the adipose tissues were collected to detect the expression level of human ALK7 mRNA by qPCR. (A) The schematic diagram of experimental processing. (B) The expression of human ALK7 mRNA in the adipose tissues. Significance was determined by t-test, P < 0.05, P < 0.01, *** P < 0.001. Values are expressed as mean ± SEM.

High-Fat Diet-Induced B-hALK7 mice. B-hALK7 mice were fed with high-fat diet (60 kcal% Fat) for 14 weeks to induce obesity. The human ALK7 targeted nucleic acid drugs (synthesized according to patents), Semaglutide and PBS were administered to the mice individually.

High-Fat Diet-Induced B-hALK7 mice. B-hALK7 mice were fed with high-fat diet (60 kcal% Fat) for 14 weeks to induce obesity. The human ALK7 targeted nucleic acid drugs (synthesized according to patents), Semaglutide and PBS were administered to the mice individually. (A) Body weight changes after induction. (B-C) Body weight changes after treatment. Values are expressed as mean ± SEM.

High-Fat Diet-Induced B-hALK7 mice. B-hALK7 mice were fed with high-fat diet (60 kcal% Fat) for 14 weeks to induce obesity. The human ALK7 targeted nucleic acid drugs (synthesized according to patents), Semaglutide and PBS were administered to the mice individually. (A-B) Lean tissues changes after induction. (C-D) Fat tissues changes after treatment. Values are expressed as mean ± SEM. Significance was determined by one-way ANOVA, *P < 0.05, P < 0.01, ***P < 0.001.

High-Fat Diet-Induced B-hALK7 mice. B-hALK7 mice were fed with high-fat diet (60 kcal% Fat) for 14 weeks to induce obesity. The human ALK7 targeted nucleic acid drugs (synthesized according to patents), Semaglutide and PBS were administered to the mice individually. The adipose tissues were collected at Day 67 to detect the expression level of human ALK7 mRNA by qPCR. All results were normalized to G2. Values are expressed as mean ± SEM.

Q1: What are ALK7 humanized mice?

A1: ALK7 humanized mice are genetically engineered mice expressing human ACVR1C/ALK7 under the endogenous mouse Alk7 promoter, enabling translational metabolic disease and obesity research.

Q2: Why is ALK7 considered an important therapeutic target?

A2: ALK7 regulates adipose metabolism and lipolysis. Human genetic studies have linked ALK7 loss-of-function variants with favorable lipid metabolism and reduced obesity risk.

Q3: Can ALK7 humanized mice be used for siRNA drug evaluation?

A3: Yes. This model is specifically designed for preclinical evaluation of human ALK7-targeted nucleic acid therapeutics, including siRNA drugs.

Q4: Does the model express endogenous mouse Alk7?

A4: No. Endogenous mouse Alk7 transcription and translation are disrupted, while human ALK7 is expressed under physiological regulatory control.

Q5: What tissues express human ALK7 in this model?

A5: Human ALK7 expression has been validated in multiple adipose tissues, including subcutaneous fat, perigonadal fat, brown fat, and perirenal fat.