Question

What is/are the phenotypes when SALL4 gene is mutated at the cellular level? How does this genotype affect the phenotype of the cell?

Answer 1

SALL4 is a zinc finger transcription factor required for proliferation of inner cell mass in blastocyst. In humans, Okihiro syndrome or Duane- radial ray syndrome is caused by mutation in SALL4. This disorder is autosomal dominant and is characterized by deafness, Duane anomaly (eye movement), skeletal defects (radial ray malformations), hearing loss, heart (atrial septal defect) and kidney abnormalities.

Homozygous mutation in SALL4 gene results in embryonic lethality as the inner cell mass will fail to develop. SALL4 is expressed in inner cell mass and trophectoderm in mouse blastocyst. SALL4 is possibly a target of the canonical Wnt beta catenin signaling. It is known to interact with other transcription factors such as Sall1 and Tbx. SALL4 interacts with TBX5 in cardiac cells and PLZK in spermatogonial progenitors (testis). It is also involved in DNA repair processes where it stabilizes Mre11–Rad50–Nbs1 complex via interaction with Rad50.

These interactions are required for kidney, limb, brain, heart etc developments. It is a part of an interconnected autoregulatory loop consisting of Oct4, Sox2 and Nanog. SALL4 can negatively antagonize the activation function of Oct4. This helps to regulate its own expression. SALL4 is shows increased expression in induced pluripotent stem cell where it is hypomethylated.

PTEN is a known downstream target of SALL4 signaling due to direct interaction with NuRD complex; thereby recruit this complex to PTEN promoter. SALL4 can interact with DNA methylases and cyclin D1 to modulate repression of cellular proliferation. Thus, SALL4 can play an important role in cancer progression. SALL4 can regulate expression of EpCAM and is involved in epithelial –mesenchymal transition during cancer by regulation expression of SNAI1113, E-cadherin etc. SALL4 can also interact with Gli3 during skeletal muscle development and is also known to regulate sonic Hedgehog signaling.

Deregulation in SALL4 can hence, lead to development of various cancers such as gastric, colorectal, germ cell, endometrial, cancers, leukemia etc. SALL4 deficient inner cell mass and trophoblast cell cannot proliferate in vitro. These cells are not defective in pluripotency but stabilize embryonic stem cells in culture. The iPS with SALL4 mutation cannot differentiate into fibroblast. Thus, SALL4 mutants will exhibit defects in embryonic and trophoblast development and will cause defects in formation of major organs.