Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Using human iPS-derived in vitro models to study the role of HOX genes in musculo-skeletal development

Award Number: R01AR085672
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/08/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

Group Awards By:

View Award Description

Using human iPS-derived in vitro models to study the role of HOX genes in musculo-skeletal development - Abstract Each muscle of our body is endowed with a specific identity defined by its location, shape, organization and function. This identity is largely dependent on the HOX family of genes which controls the regional anat- omy of tissues along the body axis 3,4. Despite nearly half a century of research, our understanding of HOX genes’ function in development remains limited, primarily due to the significant functional redundancy within this gene family. The challenge lies in the inability, to date, to generate a vertebrate embryo completely devoid of HOX genes due to the complexity of the genetics involved and allele lethality. So far only very limited loss of HOX functions have been achieved in vertebrates, revealing only part of their developmental roles. We have developed new human iPS-based in vitro models recapitulating early stages of skeletal muscle development with remarkable accuracy 2,5. These cell culture systems exhibit the expected collinear expression of HOX genes, presenting an excellent platform for studying the functions of this gene family in controlling skeletal muscle development. A significant advantage of these in vitro models is their ability to circumvent the lethality associated with HOX clusters deletions in model organisms. This application proposes leveraging our human iPS-based in vitro models to investigate the cellular and molecular mechanisms underlying HOX gene function during development, focusing on somitic derivatives such as skeletal muscle as well as motoneurons. Using CRISPR-CAS9, we have created a series of HOX clusters deletions in a human iPS line, including one (HOXKO) harboring a complete deletion of all HOX clusters. This line can differentiate to the paraxial meso- derm fate but fails to form epithelial somites and cannot generate skeletal muscle under a standard myogenic differentiation protocol 6. These defects are not observed when three out of four clusters are deleted and thus require the full removal of HOX genes. Notably, these defects can be rescued by inducible expression of a sin- gle HOX gene from different paralog groups. We also showed that retinoic acid (RA) signaling, which has re- cently been implicated in somite epithelialization7 is downregulated in HOXKO somitoids. Somite formation can be rescued by exogenous RA treatment in HOXKO cells. These results suggest central roles of HOX genes in somitogenesis and myogenesis, previously masked by functional redundancy, which we propose to study here. Our proposed experiments combine sophisticated live imaging to transcriptome and epigenome analysis to identify the cellular and molecular basis of HOX function during skeletal muscle development. Additionally, we seek to investigate whether HOX genes act as pioneer factors and identify the targets they regulate during my- ogenesis. These experiments provide a unique opportunity to unravel the regulatory logic underlying HOX function in the intricate control of patterning and morphogenesis of skeletal muscle.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $683,016 )
2026	2026	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/11/2026	NEW	$683,016
														Subtotal = $683,016

Grand Total All Awards = $683,016

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Using human iPS-derived in vitro models to study the role of HOX genes in musculo-skeletal development

Award Number: R01AR085672

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/08/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer