LIM Homeodomain (LIM-HD) Genes and Their Co-Regulators in Developing Reproductive System and Disorders of Sex Development

Abstract

LIM homeodomain (LIM-HD) family genes are transcription factors that play crucial roles in a variety of functions during embryonic development. The activities of the LIM-HD proteins are regulated by the co-regulators LIM only (LMO) and LIM domain-binding (LDB). In the mouse genome, there are 13 LIM-HD genes (<i>Lhx1</i>–<i>Lhx9</i>, <i>Isl1</i>–<i>2</i>, <i>Lmx1a</i>–<i>1b</i>), 4 Lmo genes (<i>Lmo1</i>–<i>4</i>), and 2 Ldb genes (<i>Ldb1</i>–<i>2</i>). Amongst these, <i>Lhx1</i> is required for the development of the müllerian duct epithelium and the timing of the primordial germ cell migration. <i>Lhx8</i> is necessary for oocyte differentiation and <i>Lhx9</i> for somatic cell proliferation in the genital ridges and control of testosterone production in the Leydig cells. <i>Lmo4</i> is involved in Sertoli cell differentiation. Mutations in <i>LHX1</i> are associated with müllerian agenesis or Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. <i>LHX9</i> gene variants are reported in cases with disorders of sex development (DSD). Mutations in <i>LHX3</i> and <i>LHX4</i> are reported in patients with combined pituitary hormone deficiency having absent or delayed puberty. A transcript map of the <i>Lhx</i>, <i>Lmo,</i> and <i>Ldb</i> genes reveal that multiple LIM-HD genes and their co-regulators are expressed in a sexually dimorphic pattern in the developing mouse gonads. Unraveling the roles of LIM-HD genes during development will aid in our understanding of the causes of DSD.