Hypothalamic sonic hedgehog is required for cell specification and proliferation of LHX3/LHX4 pituitary embryonic precursors

Abstract

Sonic hedgehog (SHH) is an essential morphogenetic signal that dictates cell fate decisions in several developing organs in mammals. <i>In vitro</i> data suggest that SHH is required to specify LHX3⁺/LHX4⁺ Rathke's pouch (RP) progenitor identity. However, <i>in vivo</i> studies have failed to reveal such a function, supporting instead a crucial role for SHH in promoting proliferation of these RP progenitors and for differentiation of pituitary cell types. Here, we have used a genetic approach to demonstrate that activation of the SHH pathway is necessary to induce LHX3⁺/LHX4⁺ RP identity in mouse embryos. First, we show that conditional deletion of <i>Shh</i> in the anterior hypothalamus results in a fully penetrant phenotype characterised by a complete arrest of RP development, with lack of <i>Lhx3/Lhx4</i> expression in RP epithelium at 9.0 days post coitum (dpc) and total loss of pituitary tissue by 12.5 dpc. Conversely, overactivation of the SHH pathway by conditional deletion of <i>Ptch1</i> in RP progenitors leads to severe hyperplasia and enlargement of the Sox2⁺ stem cell compartment by the end of gestation.