The role of cell death in sexually dimorphic muscle development: Male‐specific muscles are retained in female bax/bak knockout mice

Abstract

The bulbocavernosus (BC) and levator ani (LA) muscles are present in males but absent or severely reduced in females, and the fate of these muscles controls the survival of motoneurons in the sexually dimorphic spinal nucleus of the bulbocavernosus. However, the mechanism underlying the sex difference in BC and LA development has been controversial. We examined the role of cell death in sexual differentiation of the bulbocavernosus BC/LA muscles in mice. Muscle development was mapped from embryonic day 16 (E16) to postnatal day 5 (P5). A sex difference (male > female) first arose on E17 (BC) or E18 (LA), and increased in magnitude postnatally. TUNEL labeling revealed dying cells in the BC and LA muscles of both sexes perinatally. However, females had a significantly higher density of TUNEL-positive cells than did males. A role for the proapoptotic factors, Bax and Bak, in BC/LA development was tested by examining mice lacking one or both of these proteins. In females lacking either Bax or Bak, the BC was absent and the LA rudimentary. Deletion of both bax and bak genes, however, rescued the BC, increased LA size ∼20-fold relative to controls, and virtually eliminated TUNEL-positive cells in both muscles. We conclude that cell death plays an essential role in sexual differentiation of the BC/LA muscles. The presence of either Bax or Bak is sufficient for cell death in the BC/LA, whereas the absence of both prevents sexually dimorphic muscle cell death.

Mechanisms and consequences of entosis

“…In metazoans, cell death hollows the amniotic cavity (Coucouvanis and Martin 1995), establishes tissue patterns (Rusconi et al 2000), eliminates developmental organs (Lee and Baehrecke 2001), and sculpts complex tissue structures like fingers (Lindsten et al 2000), mammary gland (Mailleux et al 2007), muscle (Jacob et al 2008), brain (Lindsten et al 2003), and retina (Hahn et al 2003). Cell death maintains immune function by eliminating auto-reactive cells (Rathmell et al 2002), and cell death maintains homeostasis by removing aged or damaged cells from adult tissues.…”

Sexual Differentiation of the Spinal Nucleus of the Bulbocavernosus Is Not Mediated Solely by Androgen Receptors in Muscle Fibers

“…Rats develop pronounced sex differences in the SNB neuromuscular system during a perinatal critical period (2)(3)(4). The bulbocavernosus (BC) and levator ani (LA) muscles, which attach to the base of the penis, are highly sexually dimorphic (2), and this dimorphism is due to cell death in females (5) and an increase in muscle fiber number in males (6). Similarly, the associated SNB motoneurons are greater in number and size in males (7,8).…”

Development of the External Genitalia and Their Sexual Dimorphic Regulation in Mice

“…The sexually dimorphic muscle growth and development of LA have been suggested to occur postnatally. It has been suggested that the BC/LA of the females undergo a higher apoptosis rate which leads to an underdeveloped perineum muscle in females [Jacob et al, 2008]. However, observations of the perineum region show a noticeable difference in AGD length between males and females at the embryonic stage.…”

“…The BC is a striated muscle complex inserted into the urethral bulb or bulb of the penis [Yiou et al, 2001;Zhang et al, 2008] which possesses a posterior extension known as the LA. The functions of these muscles in mice have not yet been completely studied, but equivalent structures in humans are suggested to be involved for sustaining erection (BC) and defecation (LA) [Sachs, 1982;Karacan et al, 1983;Wallach and Hart, 1983;Jacob et al, 2008]. The formation of BCs and LAs are more prominent in males than in females ( fig.…”

“…The formation of BCs and LAs are more prominent in males than in females ( fig. 3 ), and AR knockout mice exhibit a loss of these perineum muscles [Yiou et al, 2001;Jacob et al, 2008]. The sexually dimorphic muscle growth and development of LA have been suggested to occur postnatally.…”