# A long non-coding RNA Leat1 mediates the hormone responsiveness of EfnB2 during male urogenital development

## TL;DR

A new long non-coding RNA called Leat1 helps control male urogenital development by regulating a nearby gene called EfnB2.

## Contribution

Leat1 is identified as a novel regulator of EfnB2, linking it to hormone responsiveness and hypospadias in male development.

## Key findings

- Leat1 is upregulated by testosterone and interacts with EfnB2 to regulate its expression.
- Estrogen suppresses Leat1, which in turn suppresses EfnB2 expression.
- Loss of Leat1 causes severe hypospadias in mice and is conserved in human development.

## Abstract

The novel long non-coding RNA (lncRNA) Leat1 is extraordinarily conserved in both its location (syntenic with EfnB2, an essential gene in anogenital patterning) and sequence. Here we show that Leat1 is upregulated following the production of testosterone from the developing testis in mice and interacts with EfnB2, positively regulating its expression. Leat1 expression is suppressed by estrogen, which in turn suppresses the expression of EfnB2. Moreover, the loss of Leat1 leads to reduced EfnB2, resulting in a severe hypospadias phenotype. The human LEAT1 gene is also co-expressed with EFNB2 in the developing human penis, suggesting a conserved function for this gene in urethral closure. Together our data identify Leat1 as a novel molecular regulator of urethral closure and implicate it as a target of endocrine disruption in the etiology of hypospadias.

A role for long non-coding RNA Leat1 in male urogenital development, acting by regulating the function of its neighboring gene EfnB2.