Mouse Embryo With 6 Legs And No Genitals Created By Scientists – But Why?

A six-legged mouse embryo, with extra limbs in place of genitals, has been engineered by scientists. It sounds like sci-fi, we know – but the curious creature, which also has several of its internal organs outside of its body, wasn’t created intentionally. Rather, it was an unprecedented outcome of research that has, in turn, revealed how DNA’s 3D structure can affect embryo development.

It all started when developmental biologist Moisés Mallo and his colleagues were studying Tgfbr1 – a receptor protein that is particularly important in embryonic development. The team inactivated the gene responsible for producing the protein in mouse embryos that were around the halfway point of development, intending to investigate how this change affected the developing spinal cord. 

Instead, they found something unexpected: one of the bioengineered embryos had two extra legs where its genitals should be.

“I didn’t choose the project, the project chose me,” Mallo told Nature of the surprising turn the research took.

During embryonic development, the body is made in stages, starting from the head and ending in the tail. In the first transitional stage, there is a switch from head to trunk development; and in the second, from trunk to tail. This latter transition involves significant reorganization of embryonic structures.

Tgfbr1 – or transforming growth factor-beta receptor type 1, to use its full name – is known to play a key role in trunk-to-tail transition, and also in controlling the formation of the hindlimbs and external genitalia.

It is also widely accepted that, in most four-limbed animals, external genitalia and hind limbs develop from the same early (primordial) structures.

Investigating the six-legged mouse phenomenon, Mallo and co-authors discovered that Tgfbr1 helps dictate whether these structures become either genitals or limbs. It does this, they realized, by altering the way that DNA folds in the structure’s cells. As a result, deactivation of the protein changes the expression of other genes – in this strange case, at least, that meant additional limbs and no genitalia.

3D reconstruction of the mouse embryo with Tgfbr1 deactivated. Normal limbs are in turquoise and extra limbs are in magenta.
Image credit: Lozovska et al., Nature Communications, 2024 (CC BY 4.0)

“We show that despite long evolutionary distance from the ancestral condition, the early primordium of the mouse external genitalia preserved the capacity to take hindlimb fates,” the researchers explain in their paper.

They now hope to explore whether Tgfbr1 can alter DNA structure in other systems, and if it has a role to play in the development of the reptilian “double penis” known as a hemipenis.

“Our work uncovers a remarkable tissue plasticity with potential implications in the evolution of the hindlimb/genital area of tetrapods [four-limbed vertebrates], and identifies an additional mechanism for Tgfbr1 activity that might also contribute to the control of other physiological or pathological processes,” they conclude.

In search of another six-legged developmental wonder? Meet Ariel the “mermaid” dog: born with six limbs (and a second vulva), she’s now down to the usual four after successful surgery to remove the extras.

The study is published in the journal Nature Communications.

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